2-oxoquinazoline derivatives as methionine adenosyltransferase 2a inhibitors

ABSTRACT

Disclosed herein are certain 2-oxoquinazoline derivatives of Formula (IA):that are methionine adenosyltransferase 2A (MAT2A) inhibitors. Also disclosed are pharmaceutical compositions comprising such compounds and methods of treating diseases treatable by inhibition of MAT2A such as cancer, including cancers characterized by reduced or absence of methylthioadenosine phosphorylase (MTAP) activity.

CROSS-REFERENCES TO RELATED APPLICATIONS

This is Application is the U.S. National Stage Entry under § 371 ofInternational Application No. PCT/US2019/065260, filed Dec. 9, 2019,which claims priority benefit under 35 U.S.C. § 119(e) of U.S.Provisional Application No. 62/777,715 filed Dec. 10, 2018, U.S.Provisional Application No. 62/835,853 filed Apr. 18, 2019, and U.S.Provisional Application No. 62/883,945 filed Aug. 7, 2019, the contentsof each are incorporated by reference in their entirety for allpurposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER FEDERALLY SPONSOREDRESEARCH AND DEVELOPMENT

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REFERENCE TO A “SEQUENCE LISTING,” A TABLE, OR A COMPUTER PROGRAMLISTING APPENDIX SUBMITTED ON A COMPACT DISK

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BACKGROUND OF THE INVENTION

Cancer is a leading cause of death throughout the world. A limitation ofprevailing therapeutic approaches, e.g. chemotherapy and immunotherapyis that their cytotoxic effects are not restricted to cancer cells andadverse side effects can occur within normal tissues. Consequently,novel strategies are needed to better target cancer cells.

Synthetic lethality arises when a combination of deficiencies in theexpression of two or more genes leads to cell death, whereas adeficiency in only one of these genes does not. The concept of syntheticlethality originates from studies in drosophila model systems in which acombination of mutations in two or more separate genes leads to celldeath (in contrast to viability, which occurs when only one of the genesis mutated or deleted). More recently, a multitude of studies haveexplored maladaptive genetic changes in cancer cells that render themvulnerable to synthetic-lethality approaches. These tumor-specificgenetic defects lead to the use of targeted agents that induce the deathof tumor cells while sparing normal cells.

Methionine adenosyltransferase 2A (MAT2A) is an enzyme that utilizesmethionine (Met) and adenosine triphosphate (ATP) to generate s-adenosylmethionine (SAM). SAM is a primary methyl donor in cells used tomethylate several substrates including DNA, RNA and proteins. Onemethylase that utilizes SAM as a methyl donor, is protein arginineN-methyltransferase 5 (PRMT5). While SAM is required for PRMT5 activity,PRMT5 is competitively inhibited by 5′methylthioadenosine (MTA). SinceMTA is part of the methionine salvage pathway, cellular MTA levels staylow in a process initiated by methylthioadenosine phosphorylase (MTAP).

MTAP is in a locus on chromosome 9 that is often deleted in cells ofpatients with cancers from several tissues of origin including centralnervous system, pancreas, esophageal, bladder and lung (cBioPortaldatabase). Loss of MTAP results in the accumulation of MTA makingMTAP-deleted cells more dependent on SAM production, and thus MAT2Aactivity, compared to cells that express MTAP. In an shRNA cell-linescreen across approximately 400 cancer cell lines, MAT2A knockdownresulted in the loss of viability in a larger percentage of MTAP-deletedcells compare to MTAP WT cells (see McDonald et. al. 2017 Cell 170,577-592). Furthermore, inducible knockdown of MAT2A protein decreasedtumor growth in vivo (see Marjon et. al., 2016 Cell Reports 15(3),574-587). These results indicate that MAT2A inhibitors may provide anovel therapy for cancer patients including those with MTAP-deletedtumors.

SUMMARY

Disclosed herein are certain 2-oxoquinazoline derivatives that aremethionine adenosyltransferase 2A (MAT2A) inhibitors. Also disclosed arepharmaceutical compositions comprising such compounds and methods oftreating diseases treatable by inhibition of MAT2A such as cancer,including cancers characterized by reduced or absence ofmethylthioadenosine phosphorylase (MTAP) activity.

In a first aspect, provided is a compound of Formula (IA′):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,        halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino,        heterocyclyl, heterocyclyloxy, heterocyclylamino,        heterocyclylalkyloxy, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,        or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

-   -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy,        cycloalkyl, cyano, amino, alkylamino, dialkylamino,        aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl;        provided that: (i) no more than two of w, x, y, and z can be N        and (ii) at least one of R³, R⁴, R⁵, and R⁶ is other than        hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl,        thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl,        alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹²where X^(c) is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl, provided that when R¹ is heterocyclyl and oneR^(d) and R^(e) is hydroxy, then R^(f) is not hydroxy; or

a pharmaceutically acceptable salt thereof; provided that:

(1) when

is R⁶ where: (a) when R² is chloro, piperazin-1-yl,2-methylpiperazin-1-yl, or 1H-benzo[d][1,2,3]triazol-1-yl, R³ and R⁶ arehydrogen, R⁴ is chloro and R⁵ is bromo or 5-methylindazol-4-yl, then R¹is not 2-isopropylphenyl; (b) when R² is furan-2-yl, thien-2-yl, methyl,or butyl, R³, R⁴, and R⁶ are hydrogen, and R⁵ is methyl, then R¹ is notisopropyl; (c) when R² is hydrogen, R³, R⁵, and R⁶ are hydrogen, and R⁴is chloro, then R¹ is not benzyl; (d) when R² is hydrogen, R³, R⁵, andR⁶ are hydrogen, and R⁴ is bromo, then R¹ is not 2-morpholin-4-ylethyl;(e) when R² is cyclopropyl, methyl, difluoromethyl, or pentafluoroethyl,R³, R⁵, and R⁶ are hydrogen, and R⁴ is chloro or fluoro, then R¹ is not4-methoxybenzyl; (f) when R² is cyclohexyl, pyridin-2-yl, or furan-2-yl,R³, R⁵, and R⁶ are hydrogen, and R⁴ is chloro, then R¹ is notcyclopropylmethyl; (g) when R² is hydrogen or thien-2-yl, R³, R⁵, and R⁶are hydrogen, and R⁴ is methoxy; or R² is thien-2-yl, R³, R⁴, and R⁶ arehydrogen, and R⁵ is methyl, then R¹ is not cyclopropylmethyl or2,2,2-trifluoroethyl; (h) when R² and R⁶ are methyl and R³, R⁴, and R⁵are hydrogen; or R² and R³ are methyl and R⁴, R⁵, and R⁶ are hydrogen,then R¹ is not 2,5-, 2,6- or 2,8-dimethylquinolin-4-yl or2-methyl-5-methoxy-, 2-methyl-6-methoxy- or2-methyl-8-methoxyquinolin-4-yl; (i) when R² is trifluoromethyl, R³ ismethoxy or methyl, and R⁴, R⁵, and R⁶ are hydrogen; or R² istrifluoromethyl, R³ is fluoro or hydrogen, R⁴ is halo, methyl, methoxy,isopropyl, or trifluoromethyl, and R⁵ and R⁶ are hydrogen, then R¹ isnot 4-methoxybenzyl or napth-1-ylmethyl; (j) when R² and R³ are chloroand R⁴, R⁵, and R⁶ are hydrogen; or R² is trifluoromethyl, R³ is chloro,and R⁴, R⁵, and R⁶ are hydrogen; or R⁴ is amino, R³, R⁵ and R⁶ arehydrogen, and R² is 1-methyl-1-pyrimidin-2-ylethylamino,1-cyclopropylethylamino, 1-pyrimidin-2-ylethylamino,2-hydroxy-1-methylethylamino, or 3-hydroxy-1-methylpropylamino; or R³ ismethoxy, R⁴, R⁵ and R⁶ are hydrogen, and R² is2-methyl-2-phenylpropylamino; or R⁴ is chloro, R³, R⁵ and R⁶ are H, andR² is 1-napth-2-ylmethylpiperidin-4-ylamino,1-ethoxycarbonylpiperidin-4-ylamino, or1-quinoline-6-ylmethylpiperidin-4-ylamino, then R¹ is not methyl; (k)when R² is methyl, R³ and R⁶ are hydrogen, and R⁴ and R⁵ are methoxy,then R¹ is not methyl, 2-pyridin-2-ylethyl or 3-phenylpropyl; (l) whenR² is trifluoromethyl, R³, R⁵, and R⁶ are hydrogen, and R⁴ is chloro,methoxy, or fluoro, then R¹ is not benzyl, 4-methylbenzyl or3,5-dimethylbenzyl; (m) when R² is methyl, R³, R⁵, and R⁶ are hydrogen,and R⁴ is bromo, then R¹ is not ethyl; (n) when R² is4-methoxycyclohexylamino, R³, R⁵, and R⁶ are hydrogen, and R⁴ is iodo;or R² is methyl, R³ and R⁴ are methoxy, and R⁵ and R⁶ are hydrogen; thenR is not methyl; (o) when R² is amino or acetylamino, R⁴ isdimethylamino, and R³, R⁵, and R⁶ are hydrogen, then R is not4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (p) when R⁴ is chloro,R³, R⁵ and R⁶ are hydrogen, and R is 2,2,2-trifluoroethyl, then R² isnot 1-ethoxycarbonylpiperidin-4-ylamino or8-azabicyclo[3.2.1]ocy-3ylamino; (q) when R⁵ is fluoro, R³, R⁴ and R⁶are hydrogen, and R² is -4-aminocarbonylmethyl-2-methylphenylamino, thenR¹ is not 4-fluoro-2-(2-thiazol-2-ylmethoxy)phenyl,4-fluoro-2-(2-pyridin-2-ylmethoxy)phenyl, or 4-chloro-2-methoxyphenyl;(r) when R⁶ is fluoro, R³, R⁴ and R⁵ are hydrogen, and R² is4-aminocarbonylmethyl-2-methylphenylamino, then R¹ is not4-fluoro-2-methoxyphenyl; (s) when R¹ is 4-chloro-2-ethoxyphenyl, R⁵ isfluoro, and R³, R⁴ and R⁶ are hydrogen, then R² is not3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; and (t) when R⁴ ischloro, R³, R⁵ and R⁶ are hydrogen, and R¹ is pentyl, then R² is not1-napth-1-ylmethylpiperidin-4-ylamino,1-napth-2-ylmethylpiperidin-4-ylamino, or1-ethoxycarbonylpiperidin-4-ylamino.

(2) when

then (a) when R² is hydrogen, R³ and R are methyl, and R⁴ is hydrogen,then R¹ is not 2-dimethylaminoethyl or 2-diisopropylaminoethyl; (b) whenR² is chloro, R³ is 3-pentyloxy, R⁴ is hydrogen, and R⁵ is methyl, thenR¹ is not 2,4,6-trimethylphenyl; (c) when R² is cyclohexyl, 3-hydroxy-or 4-hydroxycyclohexyl, or 3-methylcyclohexyl, R³ and R⁴ are hydrogen,and R⁵ is methyl, hydroxymethyl, or ethyl, then R¹ is not ethyl; (d)when R² and R³ are hydrogen, R⁴ is cyano, and R⁵ is amino, then R¹ isnot allyl, benzyl, methyl, or ethyl;

(3) when

then (a) when R² is hydrogen, R³ is chloro, and R⁵ is1,3-dihydroxyprop-2-ylamino, 3-diethylaminopropylamino, or4-(4-methylpiperidin-1-yl)piperidin-1-yl, then R¹ is not2,4-difluorophenyl, 2,6-difluorophenyl or 4-trifluoromethylphenyl; (b)when R² and R³ are hydrogen and R⁵ is pyridin-4-ylamino, then R¹ is notcyclopentyl; (c) when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, R⁵ isamino, and R³ is methoxy; or when R¹ is 4-methoxybenzyl, R³ is methoxy,and R⁵ is amino; then R² is not amino;

(4) when

then (a) when R² and R⁵ are methoxy and R⁴ is hydrogen; or when R² ishydrogen, amino or dimethylamino and one of R⁴ and R⁵ is hydrogen, andthe other of R⁴ and R⁵ is methyl or R⁴ and R⁵ are methyl; then R is notmethyl; (b) when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, one of R⁴and R⁵ is hydrogen, and the other of R⁴ and R⁵ is methyl or both of R⁴and R⁵ are methyl, then R² is not amino;

(5) when

then (a) when R² is 4-hydroxycyclohexylamino,dimethylaminocarbonylmethylamino, or 4-(2-hydroxyethyl)piperazin-1-yl,R⁵ is chloro or 6-methoxypyridin-3-yl, and R⁶ is hydrogen, then R¹ isnot 2-ethoxyethyl and (b) when R² is 4-hydroxycyclohexylamino,4-(2-hydroxyethyl)-piperazin-1-yl, 4-hydroxypiperidin-1-yl,2-hydroxyethylamino, piperidin-4-ylamino,dimethylaminocarbonylmethylamino, or 2-morpholin-4-ylethylamino, R⁵ ischloro or 6-methoxypyridin-3-yl, and R⁶ is hydrogen, then R¹ is not2-propyloxyethyl;

(6) when

then when R² is 4-(2-hydroxyethyl)piperazin-1-yl or4-hydroxycyclohexylamino, R⁴ and R⁶ are hydrogen, and R⁵ is chloro or6-methoxypyridin-3-yl, then, R¹ is not 2-propoxyethyl; and

(7) when

then when R² is 2-isopropyloxyethylamino, 4-hydroxy-cyclohexylamino,4-(2-hydroxyethyl)piperazin-1-yl, 2-(morpholin-4-yl)ethylamino, R³ andR⁶ are hydrogen, and R⁵ is 6-methoxypyridin-3-yl, then R¹ is not2-propoxyethyl.

In one embodiment of the first aspect, provided is a compound of Formula(IA):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,        halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino,        heterocyclyl, heterocyclyloxy, heterocyclylamino,        heterocyclylalkyloxy, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,        or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

-   -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl,        cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹² where X^(c) is bond,alkylene, or heteroalkylene and R¹² is optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl, provided that when R¹ is heterocyclyl and one R^(d) andR^(e) is hydroxy, then R^(f) is not hydroxy; or

a pharmaceutically acceptable salt thereof.

In another embodiment of the first aspect, provided is a compound ofFormula (I):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or —X^(c)—R¹² whereX^(c) is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; or

a pharmaceutically acceptable salt thereof.

In a second aspect, provided is a pharmaceutical composition comprising:

(a) is a compound of Formula (IIA′):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,        halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino,        heterocyclyl, heterocyclyloxy, heterocyclylamino,        heterocyclylalkyloxy, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,        or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

-   -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy,        cycloalkyl, cyano, amino, alkylamino, dialkylamino,        aminocarbonyl, alkylaminocarbonyl, or dialkylaminocarbonyl;        provided that: (i) no more than two of w, x, y, and z can be N        and (ii) at least one of R³, R⁴, R⁵, and R⁶ is other than        hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl,        thioureidoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl,        alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹²where X^(c) is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl, provided that when R¹ is heterocyclyl and oneR^(d) and R^(e) is hydroxy, then R^(f) is not hydroxy; or

(b) a compound of Formula (IIA):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,        halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroaralkyloxy, heteroarylamino,        heterocyclyl, heterocyclyloxy, heterocyclylamino,        heterocyclylalkyloxy, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl,        or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

-   -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl,        cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹² where X^(c) is bond,alkylene, or heteroalkylene and R¹² is optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl;

(c) a compound of Formula (II):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or —X^(c)—R¹² whereX^(c) is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl;

(d) a compound of Formula (IVA):

wherein:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴, and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen and (iii) at        least one of R³, R⁴, R⁵, and R⁶ is hydrogen;    -   R¹ is five to 8 membered cycloalkyl, bridged cycloalkyl, fused        cycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl,        bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl,        wherein aryl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, and spiroheterocyclyl are unsubstituted or        substituted with R^(d), R^(e), and/or R^(f) wherein R^(d) and        R^(e) are independently selected from alkyl, haloalkyl,        haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano, carboxy,        alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl,        sulfonylamino, aminocarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido, and        R^(f) is alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo,        cyano, or —X^(c)—R¹² where X^(c) is bond, alkylene, or        heteroalkylene and R¹² is optionally substituted aryl,        optionally substituted heteroaryl, or optionally substituted        heterocyclyl; or a tautomeric form thereof; or        (e) a compound of Formula (IA′), (IA), (I), or (IV);        (or any embodiments thereof disclosed herein), or a        pharmaceutically acceptable salt thereof; and at least one        pharmaceutically acceptable excipient.

In a third aspect, provided is a method for treating a disease mediatedby MAT2A in a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula (IA′), (IA),(I), (IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosedherein), or a pharmaceutically acceptable salt thereof. In firstembodiment of the third aspect, the patient is in recognized need ofsuch treatment. In second embodiment of the third aspect and firstembodiment contained therein, the compound of Formula (IA′), (IA), (I),(IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein),or a pharmaceutically acceptable salt thereof is administered in apharmaceutical composition. In a third embodiment of the third aspectand first and second embodiments contained therein, the disease ismediated by overexpression of MAT2A. In fourth embodiment of the thirdaspect and first, second, and third embodiments contained therein, thedisease is cancer.

In a fourth aspect, provided is a method of treating a MTAP null cancerin a patient comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (IA′), (IA), (I), (IIA), (II),(IVA), or (IV) (or an embodiment thereof disclosed herein), or apharmaceutically acceptable salt thereof. In first embodiment of thefourth aspect, the patient is in recognized need of such treatment. Insecond embodiment of the fourth aspect and first embodiment containedtherein, the compound of Formula (IA′), (IA), (I), (IIA), (II), (IVA),or (IV) (or an embodiment thereof disclosed herein), or apharmaceutically acceptable salt thereof is administered in apharmaceutical composition.

In a fifth aspect, provided is a method for inhibiting the synthesis ofS-adenosyl methionine (SAM) from methionine and ATP by MAT2A in a cellcomprising contacting the cell with an effective amount of a compound ofFormula (IA′), (IA), (I), (IIA), (II), (IVA), or (IV) (or an embodimentthereof disclosed herein), or a pharmaceutically acceptable saltthereof.

In a sixth aspect, provided is a method for treating a cancer in apatient, wherein the cancer is characterized by a reduction or absenceof methylthioadenosine phosphorylase (MTAP) gene expression, the absenceof the MTAP gene, or reduced function of MTAP protein, comprisingadministering to the subject a therapeutically effective amount of acompound of Formula (IA′), (IA), (I), (IIA), (II), (IVA), or (IV) (or anembodiment thereof disclosed herein), or a pharmaceutically acceptablesalt thereof optionally in a pharmaceutical composition.

In a seventh aspect, provided is a compound of Formula (IA′), (IA), (I),(IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein),or a pharmaceutically acceptable salt thereof for inhibiting thesynthesis of S-adenosyl methionine (SAM) from methionine and ATP byMAT2A in a cell.

In an eighth aspect, provided a compound of Formula (IA′), (IA), (I),(IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein),or a pharmaceutically acceptable salt thereof for use in the treatmentof a disease in a patient, wherein the disease is mediated by theoverexpression of MAT2A.

In a ninth aspect, provided a compound of Formula (IA′), (IA), (I),(IIA), (II), (IVA), or (IV) (or an embodiment thereof disclosed herein),or a pharmaceutically acceptable salt thereof for use in the treatment acancer in a patient, wherein the cancer is characterized by a reductionor absence of methylthioadenosine phosphorylase (MTAP) gene expression,the absence of the MTAP gene, or reduced function of MTAP protein.

In a tenth aspect provided are compounds of Formula (IV):

wherein:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴, and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that:        (i) no more than two of w, x, y, and z can be N and (ii) at        least one of R³, R⁴, R⁵, and R⁶ is other than hydrogen and (iii)        at least one of R³, R⁴, R⁵, and R⁶ is hydrogen;

R¹ is five to 8 membered cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, heterocyclyl, bridged heterocyclyl, fused heterocyclyl, andspiroheterocyclyl are unsubstituted or substituted with R^(d), R^(e),and/or R^(f) wherein R^(d) and R^(e) are independently selected fromalkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano,carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,heterocyclylcarbonyl, and ureido, and R^(f) is alkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, cyano, or —X^(c)—R¹² where X^(c) isbond, alkylene, or heteroalkylene and R¹² is optionally substitutedaryl, optionally substituted heteroaryl, or optionally substitutedheterocyclyl; or a tautomeric form thereof; or

a pharmaceutically acceptable salt thereof; provided that the compoundof Formula (IV) is not wherein:

(1) R¹ is not (a) 5-hydroxymethyltetrahydrofuran-2-yl or5-hydroxymethyltetrahydro-furan-2-yl substituted with hydroxy or fluoro;(b) 3-hydroxy-4-hydroxymethylcyclopentyl; and (c)5-aminomethyltetrahydrofuran-2-yl substituted with fluoro or hydroxy;

(2) when

where: (a) when R³ and R⁵ are fluoro and R⁴ and R⁶ are hydrogen; or R⁴and R⁵ are fluoro and R³ and R⁶ are hydrogen; or R⁵ is fluoro and R³, R⁴and R⁶ are hydrogen, then R¹ is not cyclopentyl or tetrahydrofuran-3-yl;(b) when R⁵ is chloro and R³, R⁴ and R⁶ are hydrogen, then R¹ is notphenyl, 2-methoxyphenyl, 3,4-dimethylphenyl, 2,4-dimethylphenyl,3-methoxyphenyl, 3-trifluoromethylphenyl, 3-chlorophenyl,4-methoxyphenyl, 3-methylphenyl, 2-ethoxyphenyl, or 4-ethoxyphenyl; (c)when R³ is fluoro and R⁴, R⁵ and R⁶ are hydrogen, then R¹ is not4-chlorophenyl; (d) when R⁴ is bromo and R³, R⁵ and R⁶ are hydrogen,then R¹ is not 2,4-dibromophenyl or 2-bromo-4-methylphenyl; (e) when R⁴is chloro, R⁵ is bromo and R³ and R⁶ are hydrogen, then R¹ is not3-cyanophenyl, 2-isopropylphenyl, 1-methylpropylphenyl, or3-cyclopropylpyridin-4-yl; (f) when R⁴ is trifluoromethyl and R³, R⁵ andR⁶ are hydrogen, then R¹ is not 5-chloro-2-hydroxyphenyl or5-chloro-2-methoxyphenyl; (g) when R⁴ is 2,2-difluoroethoxy and R³, R⁵and R⁶ are hydrogen, then R¹ is not piperidin-4-yl; and (h) when R⁵ ismethoxy and R³, R⁴ and R⁶ are hydrogen; or R⁴ and R⁵ are fluoro, R³ ishydrogen and R⁶ is methyl, then R¹ is not phenyl;

(3) when

then (a) when R³ and R⁵ are methyl and R⁴ is hydrogen, then R¹ is not4-ethoxyphenyl; (b) when R³ is 3-pentyloxy, R⁵ is methyl and R⁴ ishydrogen, then R¹ is not 2,4,6-trimethylphenyl; (c) when R⁴ and R⁵ arechloro and R³ is hydrogen, then R¹ is not 2-isopropyl-6-methylphenyl;(d) when R⁵ is trifluoromethyl and R³ and R⁴ are hydrogen, then R¹ isnot phenyl, 4,6-dimethoxypyrimidin-2-yl or4-hydroxy-6-methoxypyrimidin-2-yl; (e) when R⁴ is amino and R³ and R⁵are hydrogen, then R¹ is not phenyl, 2-methylphenyl, 4-methylphenyl,4-fluorophenyl, 2-, 3- or 4-chlorophenyl, 4-ethylphenyl, cyclopentyl,cyclohexyl, 2,4-dimethylphenyl, 3,5-dimethylphenyl, 3,4-dimethylphenyl,or 2- or 4-methoxyphenyl; (f) when R⁴ is bromo and R³ and R⁵ arehydrogen; or R⁴ is hydrogen and one of R³ and R⁵ is methyl and the otherof R³ and R⁵ is hydrogen; or R⁴ is hydrogen and R³ and R⁵ are methyl; orR⁵ is amino, R³ and R⁴ are hydrogen; R⁵ is amino, R³ is hydrogen, and R⁴is cyano; or R⁴ is 2-hydroxyethyl, R³ is hydrogen, and R⁵ is methyl,then R¹ is not phenyl; and (g) R³ is furan-2-yl, R⁴ and R⁵ are hydrogen,then R¹ is not cyclohexyl;

(4) when

then, (a) when R⁴ and R⁵ are methyl, then R¹ is not phenyl,2-chlorophenyl, 3-chlorophenyl, 2-methoxyphenyl, 4-methylphenyl, or4-methoxyphenyl; and

(5) when

then, when R³ and R⁵ are ethylamino or chloro, then R¹ is not phenyl.

In one embodiment of the tenth aspect, w, x, y, z, R¹, R³, R⁴, R⁵, andR⁶ in Formula (IV) are as defined in Embodiments 5, 21, 22, 23, 27 to 34and subembodiments contained therein below.

Compounds of Formula (IV) are useful as intermediates for the synthesisof compounds of Formula (IA), (I), (IIA), and (II) and also inhibitMAT2A.

DETAILED DESCRIPTION

Before the present invention is further described, it is to beunderstood that the invention is not limited to the particularembodiments set forth herein, and it is also to be understood that theterminology used herein is for the purpose of describing particularembodiments only, and is not intended to be limiting.

The singular forms “a,” “an,” and “the” as used herein and in theappended claims include plural referents unless the context clearlydictates otherwise. It is further noted that the claims may be draftedto exclude any optional element. As such, this statement is intended toserve as antecedent basis for use of such exclusive terminology such as“solely,” “only” and the like in connection with the recitation of claimelements, or use of a “negative” limitation.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range, is encompassed within the invention. The upper and lowerlimits of these smaller ranges may independently be included in thesmaller ranges, and are also encompassed within the invention, subjectto any specifically excluded limit in the stated range. Where the statedrange includes one or both of the limits, ranges excluding either orboth of those included limits are also included in the invention. Unlessdefined otherwise, all technical and scientific terms used herein havethe same meaning as commonly understood by one of ordinary skill in theart to which this invention belongs.

When needed, any definition herein may be used in combination with anyother definition to describe a composite structural group. Byconvention, the trailing element of any such definition is that whichattaches to the parent moiety. For example, the composite groupalkoxyalkyl means that an alkoxy group is attached to the parentmolecule through an alkyl group.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Further,the dates of publication provided may be different from the actualpublication dates, which may need to be independently confirmed.

Definitions

Unless otherwise stated, the following terms used in the specificationand claims are defined for the purposes of this Application and have thefollowing meaning:

“Alkyl” means a linear saturated monovalent hydrocarbon radical of oneto six carbon atoms or a branched saturated monovalent hydrocarbonradical of three to six carbon atoms, e.g., methyl, ethyl, propyl,2-propyl, butyl, pentyl, and the like. It will be recognized by a personskilled in the art that the term “alkyl” may include “alkylene” groups.

“Alkylene” means a linear saturated divalent hydrocarbon radical of oneto six carbon atoms or a branched saturated divalent hydrocarbon radicalof three to six carbon atoms unless otherwise stated e.g., methylene,ethylene, propylene, 1-methylpropylene, 2-methylpropylene, butylene,pentylene, and the like.

“Alkenyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing a double bond, e.g., propenyl, butenyl, andthe like.

“Alkynyl” means a linear monovalent hydrocarbon radical of two to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbon atoms containing a triple bond, e.g., ethynyl, propynyl,butynyl, and the like.

“Alkoxy” means a —OR radical where R is alkyl as defined above, e.g.,methoxy, ethoxy, propoxy, or 2-propoxy, n-, iso-, or tert-butoxy, andthe like.

“Alkoxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one alkoxy group, as defined above,e.g., 2-methoxyethyl, 1-, 2-, or 3-methoxypropyl, 2-ethoxyethyl, and thelike.

“Alkoxyalkoxy” means a —OR radical where R is alkoxyalkyl as definedabove e.g., methoxyethyloxy, ethyloxypropyloxy, and the like.

“Alkoxyalkylamino” means a —NRR′ radical where R is hydrogen or alkyland R′ is alkoxyalkyl, each as defined above e.g., methoxyethylamino,methoxypropylamino, and the like.

“Alkylcarbonyl” means a —C(O)R radical where R is alkyl as definedherein, e.g., methylcarbonyl, ethylcarbonyl, and the like.

“Alkoxycarbonyl” means a —C(O)OR radical where R is alkyl as definedabove, e.g., methoxycarbonyl, ethoxycarbonyl, and the like.

“Alkoxycarboxyalkyl” means an alkyl radical as defined above, that issubstituted with an alkoxycarboxy group e.g., methylcarboxymethyl,ethylcarboxyethyl, and the like.

“Alkylthio” means a —SR radical where R is alkyl as defined above, e.g.,methylthio, ethylthio, and the like.

“Alkylsulfonyl” means a —SO₂R radical where R is alkyl as defined above,e.g., methylsulfonyl, ethylsulfonyl, and the like.

“Alkylsulfonylalkyl” means a -(alkylene)-SO₂R radical where R is alkylas defined above, e.g., methylsulfonylethyl, ethylsulfonylmethyl, andthe like.

“Amino” means a —NH₂.

“Alkylamino” means a —NHR radical where R is alkyl as defined above,e.g., methylamino, ethylamino, propylamino, or 2-propylamino, and thelike.

“Aminoalkyl” means a linear monovalent hydrocarbon radical of one to sixcarbon atoms or a branched monovalent hydrocarbon radical of three tosix carbons substituted with —NR′R″ where R′ and R″ are independentlyhydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, or alkylcarbonyl,each as defined herein, e.g., aminomethyl, aminoethyl,methylaminomethyl, and the like.

“Aminoalkoxy” means a —OR radical where R is aminoalkyl as defined abovee.g., aminoethyloxy, methylaminopropyloxy, dimethylaminoethyloxy,diethylaminopropyloxy, and the like.

“Aminoalkylamino” means a —NRR′ radical where R is hydrogen or alkyl andR′ is aminoalkyl, each as defined above e.g., aminoethylamino,methylaminopropylamino, dimethylaminoethylamino,diethylaminopropylamino, and the like.

“Aminocarbonyl” means a —CONH₂ radical.

“Alkylaminocarbonyl” means a —CONHR radical where R is alkyl as definedabove, e.g., methylaminocarbonyl, ethylaminocarbonyl and the like.

“Aminosulfonyl” means a —SO₂NH₂ radical.

“Aminosulfonylalkyl” means a -(alkylene)SO₂NRR′ radical where R ishydrogen or alkyl and R′ is hydrogen, alkyl, or cycloalkyl, or R and R′together with the nitrogen atom to which they are attached formheterocyclyl, as defined above, e.g., methylaminosulfonylethyl,dimethylsulfonylethyl, and the like.

“Alkylaminosulfonyl” means a —SO₂NHR radical where R is alkyl as definedabove, e.g., methylaminosulfonyl, ethylaminosulfonyl and the like.

“Aminocarbonylalkyl” means a -(alkylene)-CONRR′ radical where R′ and R″are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, oralkoxyalkyl, each as defined herein, e.g., aminocarbonylethyl,methylaminocarbonylethyl, dimethylaminocarbonylethyl, and the like.

“Aminosulfonylalkyl” means a -(alkylene)-SO₂NRR′ radical where R′ and R″are independently hydrogen, alkyl, haloalkyl, hydroxyalkyl, oralkoxyalkyl, each as defined herein, e.g., aminosulfonylethyl,methylaminosulfonylethyl, dimethylaminosulfonylethyl, and the like.

“Aryl” means a monovalent monocyclic or bicyclic aromatic hydrocarbonradical of 6 to 10 ring atoms e.g., phenyl or naphthyl.

“Aralkyl” means a -(alkylene)-R radical where R is aryl as defined abovee.g., benzyl, phenethyl, and the like.

“Bridged cycloalkyl” means a saturated monocyclic 5- to 7-memberedhydrocarbon radical in which two non-adjacent ring atoms are linked by a(CRR′)n group where n is 1 to 3 and each R is independently H or methyl(also referred to herein as the bridging group). The bridged cycloalkylis optionally substituted with one or two substituents independentlyselected from alkyl, halo, alkoxy, hydroxy, or cyano. Examples ofbridged cycloalkyl include but are not limited to bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, etc.

“Bridged cycloalkylalkyl” means -(alkylnene)-R radical where R isbridged cycloalkyl as defined above. Examples include, but are notlimited to, bicyclo[2.2.1]heptylmethyl, and the like.

“Bridged heterocyclyl” means a saturated monocyclic ring having 5 to 7ring carbon ring atoms in which two non-adjacent ring atoms are linkedby a (CRR′)n group where n is 1 to 3 and each R is independently H ormethyl (also may be referred to herein as “bridging” group) and furtherwherein one or two ring carbon atoms, including an atom in the bridginggroup, is replaced by a heteroatom selected from N, O, or S(O)_(n),where n is an integer from 0 to 2. Bridged heterocyclyl is optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are notlimited to, 2-azabicyclo[2.2.2]octane, quinuclidine,7-oxabicyclo[2.2.1]heptane, and the like.

“Bridged heterocyclylalkyl” means -(alkylene)-R radical where R isbridged heterocyclyl (including specific bridged heterocyclyl rings) asdefined above.

“Cycloalkyl” means a monocyclic monovalent hydrocarbon radical of threeto six carbon atoms which may be saturated or contains one double bond.Cycloalkyl may be unsubstituted or substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, hydroxy,or cyano. Examples include, but are not limited to, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, 1-cyanocycloprop-1-yl,1-cyanomethylcycloprop-1-yl, 3-fluorocyclohexyl, and the like. Whencycloalkyl contains a double bond, it may be referred to herein ascycloalkenyl.

“Cycloalkylalkyl” means -(alkylene)-R radical where R is cycloalkyl asdefined above. Examples include, but are not limited to,cyclopropylmethyl, cyclobutylmethyl, and the like.

“Cycloalkylalkyloxy” means —O—R radical where R is cycloalkylalkyl asdefined above. Examples include, but are not limited to,cyclopropylmethyloxy, cyclobutylmethyloxy, and the like.

“Cycloalkyloxyalkyl” means -(alkylene)-OR radical where R is cycloalkylas defined above. Examples include, but are not limited to,cyclopropyloxymethyl, cyclopropyloxyethyl, cyclobutyloxyethyl, and thelike.

“Cycloalkylsulfonylamino” means —NRSO₂—R′ radical where R is hydrogen oralkyl and R′ is cycloalkyl, each as defined above. Examples include, butare not limited to, cyclopropylsulfonylamino,N-cyclopropylsulfonylN(CH₃), and the like.

“Cyanoalkyl” means an alkyl radical as defined above, that issubstituted with a cyano group, e.g., cyanomethyl, cyanoethyl, and thelike.

“Carboxy” means —COOH radical.

“Carboxyalkyl” means an alkyl radical as defined above, that issubstituted with a carboxy group e.g., carboxymethyl, carboxyethyl, andthe like.

“Deuteroalkyl” means alkyl radical, as defined above, wherein one to sixhydrogen atoms in alkyl chain are replaced by deuterium atoms. Examplesinclude, but are not limited to, —CD₃, —CH₂CHD₂, and the like.

“Dialkylamino” means a —NRR′ radical where R and R′ are alkyl as definedabove, e.g., dimethylamino, methylethylamino, and the like.

“Dialkylaminocarbonyl” means a —CONRR′ radical where R and R′ are alkylas defined above, e.g., dimethylaminocarbonyl, diethylaminocarbonyl andthe like.

“Dialkylaminosulfonyl” means a —SO₂NRR′ radical where R and R′ are alkylas defined above, e.g., dimethylaminosulfonyl, diethylaminosulfonyl andthe like.

“Fused cycloalkyl” means a saturated monovalent hydrocarbon radical ofthree to six carbon atoms that is fused to phenyl or a five- orsix-membered heteroaryl ring, as defined herein, and is optionallysubstituted with one, two, or three substituents independently selectedfrom alkyl, halo, alkoxy, haloalkyl, haloalkoxy, hydroxy, and cyano.Examples include, but are not limited to, tetrahydronaphthyl,4,5,6,7-tetrahydro-1H-indolyl, 4,5,6,7-tetrahydrobenzoxazolyl, and thelike.

“Fused heterocyclyl” means heterocyclyl as defined herein that is fusedto cycloalkyl, phenyl or a five- or six-membered heteroaryl ring, asdefined herein. Fused heterocyclyl is optionally substituted with one ortwo substituents independently selected from alkyl, halo, alkoxy,hydroxy, or cyano. Examples include, but are not limited to,4,5,6,7-tetrahydro-1H-pyrrolo[2,3-b]pyridinyl,1,2,3,4-tetrahydroquinolinyl, 3,4-dihydroquinolin-2(1H)-one, and thelike.

“Fused heterocyclylalkyl” means -(alkylene)-R radical where R is fusedheterocyclyloxy (including specific fused heterocyclyl rings) as definedabove.

“Halo” means fluoro, chloro, bromo, or iodo, preferably fluoro orchloro.

“Haloalkyl” means alkyl radical as defined above, which is substitutedwith one to five halogen atoms, such as fluorine or chlorine, includingthose substituted with different halogens, e.g., —CH₂Cl, —CF₃, —CHF₂,—CH₂CF₃, —CF₂CF₃, —CF(CH₃)₂, and the like. When the alkyl is substitutedwith only fluoro, it can be referred to in this Application asfluoroalkyl.

“Haloalkoxy” means a —OR radical where R is haloalkyl as defined abovee.g., —OCF₃, —OCHF₂, and the like. When R is haloalkyl where the alkylis substituted with only fluoro, it is referred to in this Applicationas fluoroalkoxy.

“Haloalkoxyalkyl” means an alkyl radical that is substituted withhaloalkoxy, each as defined above, e.g., trifluoromethoxyethyl, and thelike.

“Heteroalkylene” means a linear saturated divalent hydrocarbon radicalof two to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms wherein one carbon atom arereplaced with —O—, —NR—, —NR′CO—, —CONR′—, SO₂NR′—, or —NR′SO₂—, where Rand R′ are independently H or alkyl as defined herein, unless statedotherwise, e.g., —CH₂O—, —OCH₂—, —(CH₂)₂O—, —O(CH₂)₂—, —(CH₂)₂NH—,—NH(CH₂)₂—, and the like.

“Hydroxyalkyl” means a linear monovalent hydrocarbon radical of one tosix carbon atoms or a branched monovalent hydrocarbon radical of threeto six carbons substituted with one or two hydroxy groups, provided thatif two hydroxy groups are present they are not both on the same carbonatom. Representative examples include, but are not limited to,hydroxymethyl, 2-hydroxy-ethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl.

“Hydroxyalkoxy” means a —OR radical where R is hydroxyalkyl as definedabove e.g., hydroxyethyloxy, hydroxypropyloxy, and the like.

“Hydroxyalkylamino” means a —NRR′ radical where R is hydrogen or alkyland R′ is hydroxyalkyl, each as defined above e.g., hydroxyethylamino,hydroxypropylamino, and the like.

“Heteroaryl” means a monovalent monocyclic or bicyclic aromatic radicalof 5 to 10 ring atoms, unless otherwise stated, where one or more, (inone embodiment, one, two, or three), ring atoms are heteroatom selectedfrom N, O, or S, the remaining ring atoms being carbon. Non-limitingexamples of heteroaryl groups include pyridyl, pyridazinyl, pyrazinyl,pyrimindinyl, triazinyl, quinolinyl, quinoxalinyl, quinazolinyl,cinnolinyl, phthalazinyl, benzotriazinyl, purinyl, benzimidazolyl,benzopyrazolyl, benzotriazolyl, benzisoxazolyl, isobenzofuryl,isoindolyl, indolizinyl, benzotriazinyl, thienopyridinyl,thienopyrimidinyl, pyrazolopyrimidinyl, imidazopyridines,benzothiaxolyl, benzofuranyl, benzothienyl, indolyl, quinolyl,isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridinyl, imidazolyl,triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiadiazolyl, pyrrolyl,thiazolyl, furyl, thienyl, and the like. As defined herein, the terms“heteroaryl” and “aryl” are mutually exclusive. When the heteroaryl ringcontains 5- or 6 ring atoms it is also referred to herein as 5- or6-membered heteroaryl.

“Heteroaralkyl” means a -(alkylene)-R radical where R is heteroaryl(including specific rings) as defined above.

“Heteroaryloxy” means —OR where R is heteroaryl (including specificrings) as defined above.

“Heteroaralkyloxy” means a —O-(alkylene)-R radical where R is heteroaryl(including specific rings) as defined above.

“Heteroarylcarbonyl” means —COR where R is heteroaryl (includingspecific rings) as defined above.

“Heteroarylamino” means —NRR′ where R is hydrogen or alkyl and R′ isheteroaryl (including specific rings) as defined above.

“Heterocyclyl” means a saturated or unsaturated monovalent monocyclicgroup of 4 to 8 ring atoms in which one or two ring atoms are heteroatomselected from N, O, or S(O)₁, where n is an integer from 0 to 2, theremaining ring atoms being C. Additionally, one or two ring carbon atomsin the heterocyclyl ring can optionally be replaced by a —CO— group.More specifically the term heterocyclyl includes, but is not limited to,azetidinyl, oxetanyl, pyrrolidino, piperidino, homopiperidino,2-oxopyrrolidinyl, 2-oxopiperidinyl, morpholino, piperazino,tetrahydro-pyranyl, thiomorpholino, and the like. When the heterocyclylring is unsaturated it can contain one or two ring double bonds providedthat the ring is not aromatic. When heterocyclyl contains at least onenitrogen atom, it may be referred to herein as heterocycloamino.

“Heterocyclylalkyl” means -(alkylene)-R radical where R is heterocyclyl(including specific heterocyclyl rings) as defined above. For example,oxetanylethyl, piperidinylethyl, and the like.

“Heterocyclyloxy” means —OR radical where R is heterocyclyl (includingspecific heterocyclyl rings) as defined above.

“Heterocyclylalkyloxy” means —O-(alkylene)-R radical where R isheterocyclyl (including specific heterocyclyl rings) as defined above.For example, oxetanylethyloxy, piperidinylethyloxy, and the like.

“Heterocyclylcarbonyl” means —COR where R is heterocyclyl (includingspecific rings) as defined above.

“Heterocyclylamino” means —NRR′ radical where R is hydrogen or alkyl andR′ is heterocyclyl (including specific heterocyclyl rings) as definedabove.

“Heterocyclyloxyalkyl” means -(alkylene)-OR radical where R isheterocyclyl (including specific heterocyclyl rings) as defined above.For example, oxetanyloxyethyl, piperidinyloxyethyl, and the like.

“Heterocyclyloxyalkoxy” means —O-(alkylene)-R radical where R isheterocyclyloxy (including specific heterocyclyl rings) as definedabove. For example, oxetanyloxyethyloxy, piperidinyloxyethyloxy, and thelike.

“Heterocyclyloxyalkylamino” means —NR-(alkylene)-R′ radical where R ishydrogen or alkyl and R′ is heterocyclyloxy (including specificheterocyclyl rings) as defined above. For example,oxetanyloxyethylamino, piperidinyloxyethylamino, and the like.

“Oxo,” as used herein, alone or in combination, refers to ═(O).

“Pharmaceutically acceptable salts” as used herein is meant to includesalts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds disclosed hereincontain relatively acidic functionalities, base addition salts can beobtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent. Examples of salts derived frompharmaceutically-acceptable inorganic bases include aluminum, ammonium,calcium, copper, ferric, ferrous, lithium, magnesium, manganic,manganous, potassium, sodium, zinc and the like. Salts derived frompharmaceutically-acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N′-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. When compounds of the presentinvention contain relatively basic functionalities, acid addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired acid, either neat or in a suitableinert solvent. Examples of pharmaceutically acceptable acid additionsalts include those derived from inorganic acids like hydrochloric,hydrobromic, nitric, carbonic, monohydrogen carbonic, phosphoric,monohydrogen phosphoric, dihydrogen phosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as thesalts derived from relatively nontoxic organic acids like acetic,propionic, isobutyric, malonic, benzoic, succinic, suberic, fumaric,mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric,methanesulfonic, and the like. Also included are salts of amino acidssuch as arginate and the like, and salts of organic acids likeglucuronic or galactunoric acids and the like (see, for example, Berge,S. M., et al, “Pharmaceutical Salts”, Journal of Pharmaceutical Science,1977, 66, 1-19). Certain specific compounds of the present inventioncontain both basic and acidic functionalities that allow the compoundsto be converted into either base or acid addition salts.

The neutral forms of the compounds may be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

The present disclosure also includes protected derivatives of compoundsof the present disclosure. For example, when compounds of the presentdisclosure contain groups such as hydroxy, carboxy, thiol or any groupcontaining a nitrogen atom(s), these groups can be protected with asuitable protecting groups. A comprehensive list of suitable protectivegroups can be found in T. W. Greene, Protective Groups in OrganicSynthesis, 5^(th) Ed., John Wiley & Sons, Inc. (2014), the disclosure ofwhich is incorporated herein by reference in its entirety. The protectedderivatives of compounds of the present disclosure can be prepared bymethods well known in the art.

The present disclosure also includes prodrugs of the compound of Formula(I) (IA), (II), (IIA) and (IVA) and (IV), or a pharmaceuticallyacceptable salt thereof. Prodrugs of the compounds described herein arethose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. An example, without limitation, of a prodrug would be acompound which is administered as an ester (the “prodrug”), but then ismetabolically hydrolyzed to the carboxylic acid, the active entity.Additionally, prodrugs can be converted to the compounds of the presentinvention by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to the compounds of thepresent invention when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

Certain compounds of Formulae (I) (IA), (II), (IIA) and (IVA) and (IV)can exist in unsolvated forms as well as solvated forms, includinghydrated forms. In general, the solvated forms are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention. Certain compounds of Formulae (I) (IA), (II),(IIA) and (IVA) and (IV) may exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present disclosure and are intended to be within thescope of the present disclosure.

Certain compounds of Formulae (I) (IA), (II), (IIA) and (IVA) and (IV)possess asymmetric carbon atoms (optical centers) or double bonds; theracemates, diastereomers, geometric isomers, regioisomers and individualisomers (e.g., separate enantiomers) are all intended to be encompassedwithin the scope of the present invention. When a stereochemicaldepiction is shown, it is meant to refer the compound in which one ofthe isomers is present and substantially free of the other isomer.‘Substantially free of’ another isomer indicates at least an 80/20 ratioof the two isomers, more preferably 90/10, or 95/5 or more. In someembodiments, one of the isomers will be present in an amount of at least99%.

The compounds of Formulae (I) (IA), (II), (IIA) and (IVA) and (IV) mayalso contain unnatural amounts of isotopes at one or more of the atomsthat constitute such compounds. Unnatural amounts of an isotope may bedefined as ranging from the amount found in nature to an amount 100% ofthe atom in question. that differ only in the presence of one or moreisotopically enriched atoms. Exemplary isotopes that can be incorporatedinto compounds of the present invention, such as a compound of Formula(I) (IA), (II), (IIA) and (IVA) and (IV) (and any embodiment thereofdisclosed herein including specific compounds) include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O,¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I, and ¹²⁵I, respectively.Isotopically-labeled compounds (e.g., those labeled with ³H and ¹⁴C) canbe useful in compound or substrate tissue distribution assays. Tritiated(i.e., ³H) and carbon-14 (i.e., ¹⁴C) isotopes can be useful for theirease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability (e.g.,increased in vivo half-life or reduced dosage requirements). In someembodiments, in compounds disclosed herein, including in Table 1 belowone or more hydrogen atoms are replaced by ²H or ³H, or one or morecarbon atoms are replaced by ¹³C- or ¹⁴C-enriched carbon. Positronemitting isotopes such as ¹⁵O, ¹³N, ¹¹C, and ¹⁵F are useful for positronemission tomography (PET) studies to examine substrate receptoroccupancy. Isotopically labeled compounds can generally be prepared byfollowing procedures analogous to those disclosed in the Schemes or inthe Examples herein, by substituting an isotopically labeled reagent fora non-isotopically labeled reagent.

“Optionally substituted aryl” means aryl that is optionally substitutedwith one, two, or three substituents independently selected from alkyl,cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy,alkylsulfonyl, amino, alkylamino, dialkylamino, halo, haloalkyl,haloalkoxy, and cyano.

“Optionally substituted heteroaryl” means heteroaryl as defined abovethat is optionally substituted with one, two, or three substituentsindependently selected from alkyl, alkylsulfonyl, cycloalkyl, carboxy,alkoxycarbonyl, hydroxy, alkoxy, halo, haloalkyl, haloalkoxy, amino,alkylamino, dialkylamino, and cyano.

“Optionally substituted heterocyclyl” means heterocyclyl as definedabove that is optionally substituted with one, two, or threesubstituents independently selected from alkyl, alkylsulfonyl,cycloalkyl, carboxy, alkoxycarbonyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, aminoalkyl, halo, haloalkyl, haloalkoxy, and cyano, unlessstated otherwise.

“Pharmaceutically acceptable carrier or excipient” means a carrier or anexcipient that is useful in preparing a pharmaceutical composition thatis generally safe, non-toxic and neither biologically nor otherwiseundesirable, and includes a carrier or an excipient that is acceptablefor veterinary use as well as human pharmaceutical use. “Apharmaceutically acceptable carrier/excipient” as used in thespecification and claims includes both one and more than one suchexcipient.

“Spirocycloalkyl” means a saturated bicyclic ring having 6 to 10 ringcarbon atoms wherein the rings are connected through only one atom, theconnecting atom is also called the spiroatom, most often a quaternarycarbon (“spiro carbon”). The spirocycloalkyl ring is optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, and cyano. Representative examplesinclude, but are not limited to, spiro[3.3]heptane, spiro[3.4]octane,spiro[3.5]nonane, spiro[4.4]nonane (1:2:1:1), and the like.

“Spirocycloalkylalkyl” means -(alkylene)-R radical where R isspirocycloalkyl (including specific spirocycloalkyl) as defined above.

“Spiroheterocyclyl” means a saturated bicyclic ring having 6 to 10 ringatoms in which one, two, or three ring atoms are heteroatom selectedfrom N, O, or S(O)n, where n is an integer from 0 to 2, the remainingring atoms being C and the rings are connected through only one atom,the connecting atom is also called the spiroatom, most often aquaternary carbon (“spiro carbon”). Spiroheterocyclyl is optionallysubstituted with one or two substituents independently selected fromalkyl, halo, alkoxy, hydroxy, or cyano. Examples include, but are notlimited to, Representative examples include, but are not limited to,2,6-diazaspiro[3.3]heptane, 2,6-diazaspiro[3.4]octane,2-azaspiro[3.4]octane, 2-azaspiro[3.5]-nonane,2,7-diazaspiro[4.4]nonane, and the like.

“Spiroheterocyclylalkyl” means -(alkylene)-R radical where R isspiroheterocyclyl (including specific spiroheterocyclyl) as definedabove.

“Sulfonylamino” means a —NRSO₂R′ radical where R is hydrogen or alkyl,and R′ is alkyl, optionally substituted aryl, optionally substitutedheteroaryl, or optionally substituted heterocyclyl, each group asdefined herein.

“Substituted cycloalkyl” means a saturated monocyclic monovalenthydrocarbon radical of three to six carbon atoms that is substitutedwith one, two or three substituents where two of the three substitutentsare independently selected from alkyl, halo, alkoxy, hydroxy, haloalkyl,or haloalkoxy and the third substituent is alkyl, halo, hydroxyalkyl,haloalkyl, haloalkoxy, or cyano. Examples include, but are not limitedto, 3-hydroxy-3-trifluorocyclobutyl, 2,2-dimethyl-3-hydroxycyclobutyl,and the like.

“Substituted cycloalkylalkyl” means -(alkylene)-substituted cycloalkyl,each term is defined herein. Examples include, but are not limited to,1-hydroxymethylcycloprop-1-ylmethyl, and the like.

“About,” as used herein, is intended to qualify the numerical valueswhich it modifies, denoting such a value as variable within a margin oferror. When no particular margin of error, such as a standard deviationto a mean value given in a chart or table of data, is recited, the term“about” should be understood to mean that range which would encompass+10%, preferably +5%, the recited value and the range is included.

“Disease” as used herein is intended to be generally synonymous, and isused interchangeably with, the terms “disorder,” “syndrome,” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

“Patient” is generally synonymous with the term “subject” and as usedherein includes all mammals including humans. Examples of patientsinclude humans, livestock such as cows, goats, sheep, pigs, and rabbits,and companion animals such as dogs, cats, rabbits, and horses.Preferably, the patient is a human.

“In need of treatment” as used herein refers to a judgment made by aphysician or other caregiver that a subject requires or will benefitfrom treatment. This judgment is made based on a variety of factors thatare in the realm of the physician's or caregiver's expertise.

“Administration”, “administer” and the like, as they apply to, forexample, a patient, cell, tissue, organ, or biological fluid, refer tocontact of, for example, a compound of Formula (I), a pharmaceuticalcomposition comprising same, or a diagnostic agent to the subject, cell,tissue, organ, or biological fluid. In the context of a cell,administration includes contact (e.g., in vitro or ex vivo) of a reagentto the cell, as well as contact of a reagent to a fluid, where the fluidis in contact with the cell.

“Therapeutically effective amount” as used herein means the amount of acompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′) or asubembodiment described herein and/or a pharmaceutically acceptable saltthereof that, when administered to a patient for treating a diseaseeither alone or as part of a pharmaceutical composition and either in asingle dose or as part of a series of doses, is sufficient to affectsuch treatment for the disease. The “therapeutically effective amount”will vary depending on the compound, the disease and its severity andthe age, weight, etc., of the mammal to be treated. The therapeuticallyeffective amount can be ascertained by measuring relevant physiologicaleffects, and it can be adjusted in connection with the dosing regimenand diagnostic analysis of the subject's condition, and the like. By wayof example, measurement of the serum level of a compound of Formula (I)(or, e.g., a metabolite thereof) at a particular timepost-administration may be indicative of whether a therapeuticallyeffective amount has been used.

“Treating” or “treatment” of a disease includes:

(1) preventing the disease, i.e. causing the clinical symptoms of thedisease not to develop in a mammal that may be exposed to or predisposedto the disease but does not yet experience or display symptoms of thedisease;

(2) inhibiting the disease, i.e., arresting or reducing the developmentof the disease or its clinical symptoms; or

(3) relieving the disease, i.e., causing regression of the disease orits clinical symptoms.

“Inhibiting”, “reducing,” or any variation of these terms in relation ofMAT2A, includes any measurable decrease or complete inhibition toachieve a desired result. For example, there may be a decrease of about,at most about, or at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, orany range derivable therein, reduction of MAT2A activity compared to itsnormal activity.

“Ureido” means a —NHCONRR′ radical where R and R′ are independentlyhydrogen or alkyl, as defined above, e.g., —NHCONHmethyl, —NHCON(CH₃)₂,and the like. “Thioureidoalkyl” means a -(alkylene)-NHSO₂NRR′ radicalwhere R and R′ are independently hydrogen or alkyl, as defined above,e.g., -ethylene-NHSO₂NHmethyl, -propylene-NHSO₂NH₂, and the like.

Representative compound of Formula (I) are listed in Table 1 below:

TABLE 1 Cpd. No. Structure Name Mass Spec. 1

4,7-dichloro-1-phenylquinazolin-2(1H)- one 2

7-chloro-4-(methylamino)-1-phenyl- quinazolin-2(1H)-one 3

7-bromo-4-(methylamino)-1-phenyl- quinazolin-2(1H)-one 4

7-fluoro-1-phenylquinazolin-2(1H)-one 5

7-Chloro-1-(5-fluoro-3-hydroxy- phenyl)-4-(methylamino)-hydroquinazolin-2-one 6

7-chloro-6-fluoro-4-(methylamino)-1- phenyl-quinazolin-2(1H)-one 7

7-chloro-5-fluoro-4-(methylamino)-1- phenyl-quinazolin-2(1H)-one 8

7-chloro-4-(methylamino)-1-(pyridin-4- yl)-quinazolin-2(1H)-one 9

7-chloro-4-(methylamino)-1-(pyridin-3- yl)-quinazolin-2(1H)-one 10

7-chloro-4-(methylamino)-1-(pyridin-2- yl)-quinazolin-2(1H)-one 11

7-chloro-4-(methylamino)-1-pyrimidin- 2-yl-quinazolin-2(1H)-one 12

7-chloro-4-(methylamino)-1-(pyrazin-2- yl)-quinazolin-2(1H)-one 13

7-chloro-4-(methylamino)-1-(pyridazin- 3-yl)-quinazolin-2(1H)-one 14

7-chloro-4-(methylamino)-1- (pyrimidin-5-yl)-quinazolin-2(1H)-one 15

7-chloro-4-(methylamino)-1-(1H- pyrazol-4-yl)-quinazolin-2(1H)-one 16

7-chloro-1-(1H-imidazol-2-yl)-4- (methylamino)-quinazolin-2(1H)-one 17

7-chloro-4-(methylamino)-1-(thiazol-2- yl)-quinazolin-2(1H)-one 18

7-chloro-4-(methylamino)-1-(thiazol-5- yl)-quinazolin-2(1H)-one 19

7-chloro-4-(methylamino)-1-(1H- pyrazol-5-yl)-quinazolin-2(1H)-one 20

7-chloro-4-(cyclopropylamino)-1- phenylquinazolin-2(1H)-one 21

7-Chloro-4-(oxetan-3-ylamino)-1- phenylquinazolin-2(1H)-one 22

(S)-7-chloro-1-phenyl-4-((tetrahydro-furan-3-yl)amino)-quinazolin-2(1H)- one 23

4-(benzylamino)-7-chloro-1-phenyl- quinazolin-2(1H)-one 24

7-chloro-4-(dimethylamino)-1-phenyl- quinazolin-2(1H)-one 25

4-(azetidin-1-yl)-7-chloro-1-phenyl- quinazolin-2(1H)-one 26

(S)-7-chloro-4-(3-hydroxypyrrolidin-1- yl)-1-phenylquinazolin-2(1H)-one27

7-chloro-4-(4-methylpiperazin-1-yl)-1- phenyl-quinazolin-2(1H)-one 28

7-chloro-4-morpholino-1-phenyl- quinazolin-2(1H)-one 29

7-chloro-1-phenyl-4-(1H-pyrazol-1- yl)quinazolin-2(1H)-one 30

7-chloro-4-(ethylamino)-1-phenyl- quinazolin-2(1H)-one 31

7-chloro-4((2,2-difluoroethyl)amino)- 1-phenyl-quinazolin-2(1H)-one 32

7-chloro-1-phenyl-4-(pyridin-2-yl- amino)quinazolin-2(1H)-one 33

7-chloro-1-phenyl-4-(pyridin-4-yl- amino)quinazolin-2(1H)-one 34

7-bromo-4-(dimethylamino)-1-phenyl- quinazolin-2(1H)-one 35

4-(dimethylamino)-7-fluoro-1-phenyl- quinazolin-2(1H)-one 36

4-(dimethylamino)-7-chloro-1-(4- fluorophenyl)-hydroquinazolin-2-one 37

4-(dimethylamino)-7-chloro-1-(5- fluoro-3-hydroxyphenyl)hydro-quinazolin-2-one 38

4-azetidinyl-7-chloro-1-(5-fluoro-3-hydroxy-phenyl)hydroquinazolin-2-one 39

7-chloro-4-(cyclopropylmethylamino)-1-(3-fluorophenyl)hydroquinazolin-2- one 40

4-amino-7-chloro-1-(5-fluoro-3- hydroxyphenyl)-hydroquinazolin-2-one 41

4-amino-7-chloro-1-(4-fluorophenyl)- hydro-quinazolin-2-one 42

7,8-dichloro-4-(dimethylamino)-1- phenylquinazolin-2(1H)-one 43

7-chloro-4-(dimethylamino)-8-methyl- 1-phenyl-quinazolin-2(1H)-one 44

7-methyl-4-(methylamino)-1-phenyl- quinazolin-2(1H)-one 45

7-cyclopropyl-4-(methylamino)-1- phenylquinazolin-2(1H)-one 46

7-chloro-1-(3-hydroxyphenyl)-4- (methylamino)-hydroquinazolin-2-one 47

7-chloro-1-[3-(2-hydroxyethyl)phenyl]-4-(methylamino)-hydroquinazolin-2- one 48

7-chloro-1-[3-(3-hydroxypropyl)- phenyl]-4-(methylamino)hydro-quinazolin-2-one 49

7-methoxy-4-(methylamino)-1-phenyl- quinazolin-2 (1 H)-one 50

4-(methylamino)-2-oxo-1-phenyl-1 ,2- dihydro-quinazoline-7-carbonitrile51

4-(methylamino)-1-phenyl-7-(trifluoro- methyl)-quinazolin-2(1H)-one 52

N-(3-(7-chloro-4-(dimethylamino)-2- oxoquinazolin-1 (2H)-yl)phenyl)-methanesulfonamide 54

4-(dimethylamino)-7-chloro-1-(3- hydroxyphenyphydroquinazolin-2- one 55

7-Chloro-4-(methylamino)-1-(3- methylphenyl)hydroquinazolin-2- one 56

7-Chloro-1-(3-chlorophenyl)-4- (methylamino)hydroquinazolin-2- one 57

7-chloro-1-(2-fluorophenyl)-4- (methylamino)quinazolin-2(1H)-one 58

7-Chloro-4-(methylamino)-1-(2- methylphenyphydroquinazolin-2-one 59

4-amino-7-chloro-1-phenylquinazolin- 2(1H)-one 60

1-(3-bromophenyl)-7-chloro-4- (dimethylamino)quinazolin-2(1H)-one 61

7-chloro-1-(3-fluorophenyl)-4- (methylamino)quinazolin-2(1H)-one 62

7-chloro-4-methoxy-1-phenyl- quinazolin-2(1H)-one 63

7-chloro-4-((2-(dimethylamino)ethyl)-(methyl)-amino)-1-phenylquinazolin- 2(1H)-one 64

7-chloro-4-((2-(dimethylamino)ethyl)-amino)-1-phenylquinazolin-2(1H)-one 65

4-amino-7-chloro-1-cyclohexyl- quinazolin-2(1H)-one 66

7-chloro-1-phenyl-4-(piperidin-1-yl)- quinazolin-2(1H)-one 67

7-chloro-1-phenyl-4-(pyrrolidin-1-yl)- quinazolin-2(1H)-one 68

7-methyl-4-(methylamino)-1-phenyl- pyrido[2,3-d]pyrimidin-2(1H)-one 69

7-methyl-4-(methylamino)-1-phenyl- pyrido+4,3-d]pyrimidin-2(1H)-one 70

7-chloro-5-methoxy-4-(methylamino)- 1-phenylquinazolin-2(1H)-one 71

7-chloro-1-(3-methoxyphenyl)-4- (methylamino)quinazolin-2(1H)-one 73

7-chloro-6-methoxy-4-(methylamino)- 1-phenylquinazolin-2(1H)-one 74

7-chloro-4-(3-hydroxyazetidin-1-yl)-1- phenylquinazolin-2(1H)-one 75

7-chloro-4-(dimethylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)- one 76

4-(dimethylamino)-7-chloro-1-(3- methoxyphenyphydroquinazolin-2- one 77

4-(dimethylamino)-7-chloro-1-[3- (hydroxymethyl)phenyl]hydroquin-azolin-2-one 78

4-(dimethylamino)-7-(oxetan-3-yl)-1- phenylquinazolin-2(1H)-one 79

4-(dimethylamino)-1-phenyl-7- (tetrahydrofuran-3-yl)quinazolin-2(1H)-one 80

(R)-7-chloro-4-(3-fluoropyrrolidin-1- yl)-1-phenylquinazolin-2(1H)-one81

3-[4-(dimethylamino)-7-chloro-2- oxohydroquinazolinyl]benzenecarbonitr82

1-(7-chloro-1-(3-fluorophenyl)-2-oxo-1,2-dihydroquinazolin-4-yl)azetidine-3- carbonitrile 83

7-chloro-1-(3-fluorophenyl)-4-((3- hydroxypropyl)(methyl)amino)quina-zolin-2(1H)-one 85

5-azetidin-3-yloxy-7-chloro-4-(methyl-amino)-1-phenylhydroquinazolin-2-one m/z [M + H]+ 357.1 86

7-chloro-4-(methylamino)-1-[3- (trifluoromethyl)phenyl]hydroquinazolin-2-one m/z [M + H]+ 354.04 87

4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2- bromophenyl)-7-chlorohydroquinazolin-2-one m/z [M + H]+ 420.04 88

1-(2-chlorophenyl)-4((1-methylcyclo- propyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 395.05 89

1-(2-chlorophenyl)-4-[(2,2-difluoro- ethyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 405.1 90

1-(2-methoxypyridin-4-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 352.0 91

1-(6-methoxypyridin-2-yl)-4- (methylamino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 352.0 92

1-(4-methoxypyridin-3-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+352.0 93

1-(4-methoxypyridin-2-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+352.0 94

4,7-di(azetidin-1-yl)-1-phenylhydro- quinazolin-2-one m/z [M + H]+ 333.294

4,7-bis(dimethylamino)-1-phenylhydro- quinazolin-2-one m/z [M + H]+309.2 96

4-(methylamino)-1-phenyl-7- vinylhydro-quinazolin-2-one m/z [M + H]+278.15 97

4-(methylamino)-1-phenyl-7- propylhydroquinazolin-2-one m/z [M + H]+294.2 99

4-amino-1-(2-chlorophenyl)-7- (trifluoromethyl)hydroquinazolin-2-one m/z[M + H]+ 340.0 100

1-(2-chlorophenyl)-4-[(2,2-difluoro-ethyl)amino]-7-(trifluoromethyl)hydro- quinazolin-2-one m/z [M + H]+404.0 101

1-(2-chlorophenyl)-4-[(2,2,2-trifluoro- ethyl)amino]-7-(trifluoromethyl)hydro- quinazolin-2-one m/z [M + H]+ 422.0 102

1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 354.1 103

1-(2-chlorophenyl)-7-(trifluoromethyl)- 1,3-dihydroquinazoline-2,4-dionem/z [M + H]+ 341.0 104

7-chloro-4-(methylethyl)-1- phenylhydro-quinazolin-2-one m/z [M + H]+299.19 105

7-chloro-4-ethyl-1-phenylhydro- quinazolin-2-one m/z [M + H]+ 285.21 106

7-chloro-1-(4-methoxypyrimidin-2-yl)-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 318.12 107

3-(7-chloro-2,4-dioxo-3,4-dihydro- quinazolin-1(2H)-yl)-2-methyl-benzonitrile m/z [M + H]+ 310.13 108

3-(7-chloro-2,4-dioxo-3,4-dihydro- quinazolin-1(2H)-yl)-4-methyl-benzonitrile m/z [M + H]+ 310.06 109

7-chloro-1-(3-hydroxy-6- methylphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 316.18 110

7-chloro-1-(3-hydroxy-2- methylphenyl)-1,3-dihydroquinazoline- 2,4-dionem/z [M + H]+ 303.13 112

4-amino-7-chloro-1-phenyl-5-(1,2,3- triazol-2-yl)hydroquinazolin-2-onem/z [M + H]+ 339.11 113

7-chloro-4-(methylamino)-1-[4- (trifluoromethyl)(1,3-thiazol-2-yl)]hydroquinazolin-2-one m/z [M + H]+ 361.0 114

7-chloro-4-(methylamino)-1-(3- pyridyl)-hydroquinazolin-2-one m/z [M +H]+ 287.1 115

7-ethyl-4-(methylamino)-1- phenylhydro-quinazolin-2-one m/z [M + H]+280.1 116

7-chloro-1-(5-methyl(1,3-thiazol-2-yl))-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 307.0 117

7-chloro-1-(4-methyl(1,3-thiazol-2-yl))-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 307.0 118

1-phenyl-4-[(2,2,2- trifluoroethyl)amino]-7-(trifluoromethyphydroquinazolin-2-one m/z [M + H]+ 388.0 119

4-[(2,2-difluoroethyl)amino]-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2- one m/z [M + H]+ 370.0 120

4-methoxy-1-pyrimidin-2-yl-7- (trifluoro-methyl)hydroquinazolin-2- onem/z [M + H]+ 323.0 121

1-pyrimidin-2-yl-4-[(2,2,2-trifluoro-ethyl)amino]-7-(trifluoromethyphydro- quinazolin-2-one m/z [M + H]+390.0 122

4-[(2,2-difluoroethyl)amino]-1- pyrimidin-2-yl-7-(trifluoromethyphydro-quinazolin-2- one m/z [M + H]+ 372.0 123

4-(methylamino)-1-pyrimidin-2-yl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 322.0 124

4-amino-1-pyrimidin-2-yl-7-(trifluoro- methyl)hydroquinazolin-2-one m/z[M + H]+ 308.0 125

4-amino-1-(2-methylphenyl)-7- (trifluoromethyl)hydroquinazolin-2-one m/z[M + H]+ 320.0 126

1-(2-methylphenyl)-4-[(2,2,2-trifluoro-ethyl)amino]-7-(trifluoromethyl)hydro- quinazolin-2-one m/z [M + H]+402.0 127

4-[(2,2-difluoroethyl)amino]-1-(2- methylphenyl)-7-(trifluoromethyphydro-quinazolin-2- one m/z [M + H]+ 384.0 128

4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2- methylphenyl)-7-(trifluoromethyphydro-quinazolin-2- one m/z [M + H]+ 390.0 129

4-(methylamino)-1-(2-methylphenyl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 334.0 130

7-cyclopropyl-1-phenyl-1,3-dihydro- quinazoline-2,4-dione m/z [M + H]+279.21 132

tert-butyl 3-[7-chloro-4-(methylamino)-2-oxo-1-phenylhydroquinazolin-5-yl- oxy]azetidinecarboxylate m/z [M +H]+ 457.13 133

3-[7-chloro-4-(methylamino)-2-oxo- hydroquinazolin-1-yl]benzoicacid m/z[M + H]+ 330.11 134

3-[7-chloro-4-(methylamino)-2-oxo- hydroquinazolin-1-yl]benzamide m/z[M + H]+ 329.11 135

4-((3R)-3-hydroxypyrrolidin-1-yl)-7- chloro-1-(2-chlorophenyl)hydro-quinazolin-2-one m/z [M + H]+ 376.10 136

1-phenyl-4-((2,2,2- trifluoroethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+ 389.0137

4-((2,2-difluoroethyl)amino)-1-phenyl- 7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 371.0 138

4-amino-1-phenyl-7-(trifluoromethyl)-hydropyridino[2,3-d]pyrimidin-2-one m/z [M + H]+ 307.0 139

344-(3-hydroxyazetidinyl)-2-oxo-7- (trifluoromethyl)hydroquinazolinyl]-benzenecarbonitrile m/z [M + H]+ 387.0 140

3-[4-amino-2-oxo-7-(trifluoromethyl)-hydroquinazolinyl]benzenecarbonitrile m/z [M + H]+ 331.0 141

344((3R)-3-hydroxypyrrolidinyl)-2- oxo-7-(trifluoromethyl)hydro-quinazolinyl]-benzenecarbonitrile m/z [M + H]+ 401.1 142

3+4-(methylamino)-2-oxo-7-(trifluoro- methyl)hydroquinazolinyl]benzene-carbonitrile m/z [M + H]+ 345.1 143

7-(difluoromethyl)-4-(methylamino)-1- phenylhydroquinazolin-2-one m/z[M + H]+ 302.0 144

4-methoxy-1-phenyl-7- (trifluoromethyl)-hydroquinazolin-2- one m/z [M +H]+ 321.0 145

4-((3R)-3-hydroxypyrrolidinyl)-1- phenyl-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M + H]+ 376.0 146

4-amino-1-phenyl-7-(trifluoromethyl)- hydroquinazolin-2-one m/z [M + H]+306.0 147

1-(2-methylphenyl)-7-(trifluoromethyl)- 1,3-dihydroquinazoline-2,4-dionem/z [M + H]+ 321.0 148

4-amino-7-chloro-1-(2-chlorophenyl)- hydroquinazolin-2-one m/z [M + H]+307.06 149

4-amino-1-(2-bromophenyl)-7-chloro- hydroquinazolin-2-one m/z [M + H]+349.98 150

4-amino-7-methyl-1-phenylhydro- pyridino[2,3-d]pyrimidin-2-one m/z [M +H]+ 353.24 151

4-((3R)-3-hydroxypyrrolidin-1-yl)-7- chloro-1-(2-methoxyphenyl)hydro-quinazolin-2-one m/z [M + H]+ 372.10 153

4-((3R)-3-hydroxypyrrolidin-1-yl)-7- chloro-1-(2-chlorophenyl)hydro-quinazolin-2-one m/z [M + H]+ 376.04 154

4-amino-7-chloro-1-(2-methylphenyl)- hydroquinazolin-2-one m/z [M + H]+386.0 155

3-[7-chloro-4-(methylamino)-2-oxo- hydroquinazolinyl]benzenecarbonitrilem/z [M + H]+ 311.12 156

3-(7-chloro-4-hydroxy-2-oxohydro- quinazolinyl)benzoicacid m/z [M + H]+317.06 157

7-chloro-1-(3-hydroxy-2- methylphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 316.12 159

[1-(7-chloro-2-oxo-1-phenylhydro- quinazolin-4-yl)azetidin-3-yl]-N,N-dimethylcarboxamide m/z [M + H]+ 383.1 160

7-(chloromethyl)-4-(methylamino)-1- phenylhydroquinazolin-2-one m/z [M +H]+ 300.0 161

1-(2-chlorophenyl)-4-(3-hydroxy- azetidinyl)-7-(trifluoromethyl)pyrido-[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 397.1 162

3-(4-(3-hydroxyazetidin-1-yl)-2-oxo-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M + H]+ 388.1 163

4-amino-7-bromo-1-phenylhydro- quinazolin-2-one m/z [M + H]+ 316.0 164

4-(3-hydroxyazetidin-1-yl)-1-phenyl-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 362.0 165

4-(3-hydroxyazetidinyl)-1-(2-methyl-phenyl)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M +H]+ 377.24 166

7-(difluoromethyl)-1-phenyl-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 289.0 167

4-amino-1-(2-chlorophenyl)-7- (trifluoro-methyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 341.10 168

3-(4-amino-2-oxo-7-(trifluoromethyl)- pyrido[2,3-d]pyrimidin-1(2H)-yl)-benzonitrile m/z [M + H]+ 332.10 169

4-amino-1-(2-methylphenyl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 321.1 170

(R)-4-(3-hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 377.15 171

4-(3-hydroxyazetidin-1-yl)-1-phenyl-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 363.0 172

(S)-7-chloro-4-(2-(hydroxymethyl)- azetidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M + H]+ 342.1 173

3-[7-chloro-4-(methylamino)-2-oxo- hydroquinazolinyl]-2-methylbenzene-carbonitrile m/z [M + H]+ 325.11 174

3-(7-chloro-4-(methylamino)-2-oxo- quinazolin-1(2H)-yl)-2-methyl-benzonitrile m/z [M + H]+ 325.11 175

3-(7-chloro-4-(methylamino)-2-oxo- quinazolin-1(2H)-yl)benzamide m/z[M + H]+ 343.1 176

1-(2-chlorophenyl)-4-(pyrrolidin-1-yl)- 7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 395.10 177

3-(2-oxo-4-(pyrrolidin-1-yl)-7- (trifluoro-methyl)pyrido[2,3-d]pyrimidin-1(2H)-yl)benzonitrile m/z [M + H]+ 385.15 178

1-(2-chlorophenyl)-4-(methylamino)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 355.10 179

3-[4-(methylamino)-2-oxo-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-1(2H)- yl)benzonitrile m/z [M + H]+ 346.1180

4-(methylamino)-1-(2-methylphenyl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 335.10 181

(S)-1-(2-chlorophenyl)-4-(3-hydroxy-pyrrolidin-1-yl)-7-(trifluoromethyl)- pyrido[2,3-d]pyrimidin-2(1H)-onem/z [M + H]+ 411.10 182

(S)-3-(4-(3-hydroxypyrrolidin-1-yl)-2-oxo-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-1(2H)-yl)benzonitrile m/z[M + H]+ 402.1 183

(R)-4-(3-hydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M +H]+ 391.2 184

4-(methylamino)-1-phenyl-7- (trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 321.1 185

7-chloro-5-(2-hydroxyethoxy)-4- (methylamino)-1-phenylhydro-quinazolin-2-one m/z [M + H]+ 346.17 186

7-chloro-4-[2-(hydroxymethyl)azetidin-1-yl]-1-phenylhydroquinazolin-2-one m/z [M + H]+ 342.17 187

(R)-7-chloro-4-(2-(hydroxymethyl)- azetidin-1-yl)-1-phenylquinazolin-2(1H)-one m/z [M + H]+ 342.17 188

7-chloro-4-(methylamino)-1-(1-methyl- imidazol-2-yphydroquinazolin-2-onem/z [M + H]+ 290.0 189

(R)-7-chloro-4-(3-methoxypyrrolidin-1- yl)-1-phenylquinazolin-2(1H)-onem/z [M + H]+ 356.24 190

7-chloro-4-(methylamino)-2-oxo-1- phenylhydroquinazoline-6-carbonitrilem/z [M + H]+ 311.18 191

7-chloro-1-phenylhydroquinazolin-2- one m/z [M + H]+ 257.26 192

7-methyl-4-(methylamino)-1-phenyl- pyrido[3,2-d]pyrimidin-2(1H)-one m/z[M + H]+ 267.29 193

7-methyl-1-phenylpyrido[3,2-d]- pyrimidine-2,4(1H,3H)-dione m/z [M + H]+254.24 194

7-methyl-1-phenylpyrimido[4,5-d]- pyrimidine-2,4(1H,3H)-dione m/z [M +H]+ 254.26 195

(2S)-1-(7-chloro-2-oxo-1-phenylhydro- quinazolin-4-yl)pyrrolidine-2-carboxylicacid m/z [M + H]+ 370.12 196

(S)-7-chloro-4-(3-methoxypyrrolidin-1- yl)-1-phenylquinazolin-2(1H)-onem/z [M + H]+ 356.24 197

7-chloro-4-[methylbenzylamino]-1- phenylhydroquinazolin-2-one m/z [M +H]+ 376.24 188

2-((7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)(methyl)amino)-N-methylacetamide m/z [M + H]+ 343.10 199

methyl 1-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)azetidine-3- carboxylate m/z [M + H]+ 370.10 200

N-(7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)methane-sulfonamide m/z [M + H]+ 350.04 201

4-(3-aminopyrrolidin-1-yl)-7-chloro-1- phenylquinazolin-2(1H)-one m/z[M + H]+ 341.11 202

7-chloro-4-(methylamino)-5-oxetan-3- yloxy-1-phenylhydroquinazolin-2-onem/z [M + H]+ 358.10 203

N-(7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)acetamide m/z[M + H]+ 314.12 204

1-(7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)-N-methyl-azetidine-3-carboxamide m/z [M + H]+ 369.22 205

4-[(2,2-difluoroethyl)methylamino]-7-chloro-1-phenylhydroquinazolin-2-one m/z [M + H]+ 350.10 206

7-chloro-4-(2-oxoazetidin-1-yl)-1- phenylhydroquinazolin-2-one m/z [M +H]+ 326.17 207

4-(3,3-difluoropyrrolidin-1-yl)-7- chloro-1-phenylhydroquinazolin-2-onem/z [M + H]+ 328.17 208

7-chloro-4-(methylamino)-1-phenyl-5-(1H-pyrazol-1-yl)quinazolin-2(1H)-one m/z [M + H]+ 352.18 209

7-chloro-4-(methylamino)-1-phenyl-5-(1,2,3-triazol-2-yl)quinazolin-2(1H)- one m/z [M + H]+ 353.1 210

7-chloro-1-(4-hydroxypyrimidin-2-yl)- 1,3-dihydroquinazoline-2,4-dionem/z [M + H]+ 291.0 211

4-(dimethylamino)-7-chloro-1-(3- {[(methylcyclopropyl)sulfonyl]amino}phenyl)-hydroquinazolin-2-one m/z [M + H]+ 433.1 212

7-(hydroxymethyl)-1-phenyl-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 269.0 213

ethyl 2,4-dioxo-1-phenyl-1,3-dihydro- quinazoline-7-carboxylate m/z [M +H]+ 311.0 214

7-chloro-4-(methylamino)-1-pyrazol-5- ylhydroquinazolin-2-one m/z [M +H]+ 276.1 215

7-chloro-1-(1-methylimidazol-2-yl)-1,3- dihydroquinazoline-2,4-dione m/z[M + H]+ 277.1 216

4-((3S)-3-hydroxy-3-methylpyrrolidin- 1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M + H]+ 256.12 217

4-((3R)-3-hydroxy-3-methylpyrrolidin- 1-yl)-7-chloro-1-phenylhydroquinazolin-2-one m/z [M + H]+ 256.12 218

7-chloro-1-(2-chlorophenyl)-4- (methylamino)quinazolin-2(1H)-one m/z[M + H]+ 320.0 219

2-(7-chloro-4-(methylamino)-2-oxo- quinazolin-1(2H)-yl)benzonitrile m/z[M + H]+ 311.0 220

2-((7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)(methyl)amino)-N,N- dimethylacetamide m/z [M + H]+ 371.18 221

2-((7-chloro-2-oxo-1-phenyl-1,2- dihydroquinazolin-4-yl)(methyl)amino)-,N-methylacetamide m/z [M + H]+ 357.12 222

4-(3-azabicyclo[3.1.0]hex-3-yl)-7- chloro-1-phenylhydroquinazolin-2-onem/z [M + H]+ 338.13 223

7-chloro-4-(2-methylazetidin-1-yl)-1- phenylhydroquinazolin-2-one m/z[M + H]+ 326.13 224

(2R)-1-(7-chloro-2-oxo-1-phenylhydro- quinazolin-4-yl)pyrrolidine-2-carboxylicacid m/z [M + H]+ 370.12 225

1-(2-bromophenyl)-7-chloro-4- (methylamino)quinazolin-2(1H)-one m/z [M +H]+ 364.0 226

7-chloro-1-(2-methoxyphenyl)-4- (methylamino)hydroquinazolin-2-one m/z[M + H]+ 316.0 227

4-(dimethylamino)-7-chloro-1-[3-(3- phenylpropyl)phenyl]hydroquinazolin-2-one m/z [M + H]+ 418.2 228

4-(dimethylamino)-1-phenyl-7-(1,3- thiazol-4-yl)hydroquinazolin-2-onem/z [M + H]+ 349.0 229

7-chloro-1-(4-hydroxyphenyl)-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 289.1 230

7-chloro-4-(3-methoxypyrrolidin-1-yl)- 1-phenylquinazolin-2(1H)-one m/z[M + H]+ 356.12 231

2-[( 7-chloro-2-oxo-1 -phenyl-1,2- dihydroquinazolin-4-yl)ainino]-N,N-dimcthylacctamidc m/z [M + H]+ 357.12 232

7-chloro-4-[(oxetan-3-ylmethyl)amino]- 1-phenylhydroquinazolin-2-one m/z[M + H]+ 342.23 233

7-chloro-4-1[(1-methylpyrazo1-3-yl)- methyl]amino)-1-phenylhydro-quinazolin-2-one m/z [M + H]+ 366.24 234

7-chloro-4-[methyl(pyridin-4- ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M + H]+ 377.1 235

7-chloro-4-[methyl(pyridin-3- ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M + H]+ 377.24 236

7-chloro-4-[methyl(pyridin-2- ylmethyl)-amino]-1-phenylhydroquinazolin-2-one m/z [M + H]+ 377.12 237

7-chloro-4-[methyl(2,2,2- trifluoroethyl)-amino]-1_phenylhydroquinazolin-2-one m/z [M + H]+ 368.18 238

4-(3,3-dimethylpyrrolidin-1-yl)-7- chloro-1-phenylhydroquinazolin-2-onem/z [M + H]+ 354.12 239

4-((3R)-3-hydroxypyrrolidinyl)-7- chloro-1-phenylhydroquinazolin-2-onem/z [M + H]+ 342.19 240

(2S)-1-(7-chloro-2-oxo-1-phenylhydro- quinazolin-4-yl)pyrrolidine-2-carboxamide m/z [M + H]+ 369.18 241

(2R)-1-(7-chloro-2-oxo-1-phenylhydro- quinazolin-4-yl)pyrrolidine-2-carboxamide m/z [M + H]+ 369.19 242

7-chloro-4-methyl-1-phenylhydro- quinazolin-2-one m/z [M + H]+ 271.1 243

3-chloro-8-(methylamino)-5-phenyl-5-hydropyrimidino[5,4-c]pyridazin-6-one [M + H]+ 288.16 244

1-(2-chlorophenyl)-4-(dimethylamino)- 7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 369.05 245

1-(2-chlorophenyl)-4-(spiro[3.3]heptan-2-ylamino)-7-(trifluoromethyl)pyrido- [2,3-d]pyrimidin-2(1H)-one [M +H]+ 435.10 246

1-(2-chlorophenyl)-4-((cyclopropyl- methyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 395.05 247

1-(2-chlorophenyl)-4-[(3-hydroxy- propyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 399.05 248

1-(2-chlorophenyl)-4-[(3-methoxy- propyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 413.10 249

4-[(2,2-difluoroethyl)amino]-7-chloro-1-(4-hydroimidazo[1,2-a]pyridin-6-yl)- hydroquinazolin-2-one m/z [M +H]+ 376.0 250

4-((3R)-3-hydroxypyrrolidin-1-yl)-7- chloro-1-(4-hydroimidazo[1,2-a]pyridin-6-yl)-hydroquinazolin-2-one m/z [M + H]+ 382.00 251

7-chloro-1-(4-hydroimidazo[1,2-a]- pyridin-6-yl)-4-(methylamino)hydro-quinazolin-2-one m/z [M + H]+ 326.00 252

4-amino-7-chloro-1-(4-hydroimidazo-[1,2-a]pyridin-6-yl)hydroquinazolin-2- one m/z [M + H]+ 312.00 253

1-benzothiazol-2-yl-7-chloro-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 330.0 254

1-(1H-indazol-4-yl)-7-chloro-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 313.0 255

1-(2-chlorophenyl)-4-(3-hydroxy-3- methylpyrrolidin-1-yl)-7-(trifluoro-methyphydropyridino-[2,3-d]pyrimidin- 2-one m/z [M + H]+ 425.37 256

1-(2-chlorophenyl)-4-(2-pyridylamino)- 7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 418.35 257

1-(2-chlorophenyl)-4-{[(1-methyl- pyrazol-3-yl]methyl]amino}-7-(trifluoro-methyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 435.35258

1-(2-chlorophenyl)-4-[(methylethyl)-amino]-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 383.34 259

4-[(tert-butyl)amino]-1-(2-chloro-phenyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M +H]+ 397.39 260

1-(3-methyl(2-pyridyl))-4-(methyl- amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 336.37 261

1-(3-chloro(2-pyridyl))-4-(methyl- amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 356.36 262

7-chloro-1-(imidazol-4-ylmethyl)-4- (methylamino)hydroquinazolin-2-onem/z [M + H]+ 290.36 263

4-amino-1-(2-methyl(3-pyridyl))-7- (trifluoromethyl pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 322.10 264

1-(2-chlorophenyl)-4-{[2-(methyl- sulfonyl)ethyl]amino}-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 447.00 265

1-(2-chlorophenyl)-4-(((1-(hydroxy- methyl)cyclopropyl)methyl)amino)-7-(trifluoromethyl)-pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+ 425.00266

4-{[3-(dimethylamino)propyl]amino 1-1-(2-ch1orophenyl)-7-(trifluoromethyl)- pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 426.00 267

4-55 [2-(dimethylamino)ethyl]amino1-1-(2-chlorophenyl)-7-(trifluoromethyl)- pyrido[2,3-d]pyrimidin-2 (1H)-onem/z [M + H]+ 412.00 268

1-(2-chlorophenyl)-4-(((1s,3s)-3- hydroxy-3-methylcyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 425.00269

1-(2-chlorophenyl)-4-(((1s,3s)-3- hydroxy-1-methylcyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 425.00270

1-(2-chlorophenyl)-4-(((1s,3s)-3- methoxycyc1obutyl)amino)-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 425.00 271

1-(2-chlorophenyl)-4-[(oxetan-2- ylmethyl)amino]-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 411.00 272

4-((methyl-d3)amino)-1-(2-methyl- phenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 338.20 273

4-[((1S)-2-hydroxy-isopropyl)amino]-(1Ra)-(2-chlorophenyl)-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 399.00 274

1-(2-chlorophenyl)-4-(oxetan-3-yl- amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 397.0 275

4-{[(cis)-3-hydroxy-3-(trifluoromethyl)-cyclobutyl]amino}-1-(2-chlorophenyl)- 7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 479.00 276

4-{[(cis)-3-hydroxy-2,2-dimethylcyclo-butyl)amino}-1-(2-chlorophenyl)-7- (trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 439.00 277

1-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)cyclobutane-1-carbonitrile m/z[M + H]+ 420.00 278

3-((1-(2-chlorophenyl)-2-oxo-7- (trifluoro-methyl)-1,2-dihydropyrido-[2,3-d]pyrimidin-4-yl)amino)- propanenitrile m/z [M + H]+ 394.00 279

(R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-(1H-indazol-5-yl)quinazolin- 2(1H)-one m/z [M + H]+ 382.0 280

7-chloro-4-(dimethylamino)-1-(1H- indazol-5-yl)quinazolin-2(1H)-one m/z[M + H]+ 340.0 281

(R)-7-chloro-4-(3-hydroxypyrrolidin-1- yl)-1-(1H-benzimidazol-5-yl)quinazolin-2(1H)-one m/z [M + H]+ 382.0 282

4-((2,2-difluoroethyl)amino)-1-(2- methylpyridin-3-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 385.0 283

4-((3R)-3-hydroxypyrrolidinyl)-1-(2- methylpyridin-3-yl))-7-(trifluoromethyl)-hydroquinazolin-2- one m/z [M + H]+ 391.0 284

1-(2-methylpyridin-3-yl))-4-(methyl- amino)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M + H]+ 335.0 285

4-amino-1-(2-methylpyridin-3-yl))-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 321.0 286

1-(2-chlorophenyl)-4-morpholin-4-yl-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 411.40 287

2-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)acetamide m/z [M + H]+ 398.36288

1-(2-chlorophenyl)-4-hydroxy-7- (trifluoromethyl)hydropyridino[2,3-d]-pyrimidin-2-one m/z [M + H]+ 342.31 289

7-chloro-5-(2,5-dihydro-1H-pyrrol-3- yl)-4-hydroxy-1-phenylquinazolin-2(1H)-one m/z [M + H]+ 340.37 290

tert-butyl 3-(7-chloro-4-hydroxy-2-oxo-1-phenyl-1,2-dihydroquinazolin-5-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate m/z [M + H]+ 440.12 291

7-chloro-4-hydroxy-1-phenyl-5- (pyridin-4-yl)quinazolin-2(1H)-one m/z[M + H]+ 350.09 292

4-[((1S)-2-hydroxy-isopropyl)amino]-(1Sa)-(2-chlorophenyl)-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 399.10 293

4-[((2S)-2-hydroxypropyl)amino]-1-(2- chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 399.10 294

4-[((2R)-2-hydroxypropyl)amino]-1-(2- chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 399.10 295

1-(2-chlorophenyl)-4-{[(hydroxycyclo- propyl)methyl]amino}-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 411.10 296

1-(2-chlorophenyl)-4-[(2-hydroxy- methyl)amino]-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 385.10 297

1-(2-chlorophenyl)-4-[(3-hydroxy- bicyclo[1.1.1]pentyl)amino]-7-(trifluoro-methyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 423.10298

4-[((trans)-3-hydroxy-1-methylcyclo- butyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 425.10299

4-{[(trans)-3-hydroxy-3-(trifluoro- methyl)cyclobutyl]amino}-1-(2-chlorophenyl)-7- (trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z[M + H]+ 479.10 300

4-[((trans)-3-hydroxy-3-methylcyclo- butyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 425.10301

4-[(trans)-3-methoxycyclobutyl)amino]-1-(2-chlorophenyl)-7-(trifluoromethyl)- pyrido[2,3-d]pyrimidin-2(1H)-onem/z [M + H]+ 425.10 302

6-bromo-1-(2-chlorophenyl)-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 432.0 303

6-bromo-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 398.0 304

1(2-chlorophenyl)-6-fluoro-4-(methyl- amino)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M + H]+ 372.0 305

1-benzimidazol-7-yl-7-chloro-1,3- dihydroquinazoline-2,4-dione m/z [M +H]+ 313.0 306

1-benzimidazol-5-yl-4- (dimethylamino)-7- chlorohydroquinazolin-2-onem/z [M + H]+ 340.0 307

1-benzimidazol-5-yl-7-chloro-4- (methyl-amino)hydroquinazolin-2-one m/z[M + H]+ 326.0 308

1-(2-chlorophenyl)-4-(cyclopropyl- amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 381.28 309

7-cyclopropyl-4-(methylamino)-1- pyrimidin-2-ylhydroquinazolin-2-one m/z[M + H]+ 294.30 310

7-chloro-1-(4-fluoro-3-hydroxyphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 320.34 311

7-chloro-1-(2-fluoro-5- methoxyphenyl)-quinazoline- 2,4(1H,3H)-dione m/z[M + H]+ 321.31 312

1-(3-chloro-pyridin-4-yl))-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 356.00 313

4-(methylamino)-1-(pyridin-4-yl))-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 322.00 314

1-(6-methyl--pyridin-3-yl))-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 336.0 315

1-(2-chlorophenyl)-4-(3-fluoroazetidin-1-yl)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+399.10 316

1-(2-chlorophenyl)-4-((2,2-dioxido-2-thiaspiro[3.3]heptan-6-yl)amino)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 485.10 317

1-(2-chlorophenyl)-4-[(2- methoxyethyl)-amino]-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+ 399.10318

(1s,3s)-3-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)cyclobutane-1-carbonitrile m/z[M + H]+ 420.10 319

1-(2-chlorophenyl)-4-[(methylcyclo-butyl)amino]-7-(trifluoromethyl)pyrido- [2,3-d]pyrimidin-2(1H)-one m/z[M + H]+ 409.20 320

1-(2-chlorophenyl)-4- (cyclobutylamino)-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+ 395.10321

(1s,3s)-3-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)cyclobutane-1-carbonitrile m/z[M + H]+ 411.10 322

1-(2-chlorophenyl)-4-{[(hydroxy- methyl)cyclopropyl]amino}-7-(trifluoro-methyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 411.10323

(R)-(1Sci)-(2-chlorophenyl)-4-((1- hydroxypropan-2-yl)amino)-7-(trifluoro-methyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 399.10324

(R)-(1R,i)-(2-chlorophenyl)-4-((1- hydroxypropan-2-yl)amino)-7-(trifluoro-methyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 399.10325

4-[(2,2-difluoroethyl)amino]-1-(pyridin- 3-yl)-7-(trifluoromethyl)hydro-quinazolin-2-one m/z [M + H]+ 371.0 326

4-((3R)-3-hydroxypyrrolidinyl)-1- (pyridin-3-yl)-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M + H]+ 372.0 327

4-amino-1-(pyridin-3-yl)-7-(trifluoro- methyl)hydroquinazolin-2-one m/z[M + H]+ 307.0 328

1-(1H-indazol-5-yl)-7-chloro-4- (methyl-amino)hydroquinazolin-2-one m/z[M + H]+ 326.0 329

7-chloro-5-methoxy-4-(methylamino)- 1-(2-methylphenyl)hydroquinazolin-2-one m/z [M + H]+ 330.1 330

7-chloro-1-(4-fluoro-3- methoxyphenyl)-4- hydroxyhydroquinazolin-2-onem/z [M + H]+ 319.05 331

7-chloro-1-(6-fluoro-3-hydroxyphenyl)-4-(methylamino)hydroquinazolin-2-one m/z [M + H]+ 319.06 332

7-chloro-1-(2-fluoro-3- metho xyphenyl)-4- hydroxyhydroquinazolin-2-onem/z [M + H]+ 320.06 333

7-chloro-1-(2-fluoro-3-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 320.27 334

1-(2-chlorophenyl)-4-(((1r,30-3- hydroxycyc1obutyl)amino)-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-2 (1H)- one m/z [M + H]+ 411.00 335

4-[((2S,1R)-2-hydroxycyclobutyl)- amino]-(1S_(a))-(2-chlorophenyl)-7-(trifluoromethyl)hydro-pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+411.00 336

4-[((2S,1R)-2-hydroxycyclo- butypamino]-(1R_(a))-(2-(2-7-(trifluoromethyl)hydro-pyridino[2,3-d]- pyrimidin-2-one m/z [M + H]+411.00 337

4-[((lS,2S)-2-hydroxycyclobutyl)- amino]-(1 S a)-(2-chlorophenyl)-7-(trifluoromethyl)hydro-pyridino[2,3-d]- pyrimidin-2-one m/z [M + H]+411.00 338

4-[((lS,2S)-2-hydroxycyclobutyl)- amino]-(1Ra)-(2-chlorophenyl)-7-(trifluoromethyl)hydro-pyridino[2,3-d]- pyrimidin-2-one m/z [M + H]+411.00 339

4-(bis(methyl-d3)amino)-1-(2-chloro-phenyl)-7-(trifluoromethyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M +H]+ 375.00 340

1 -(1H-benzo[d]imidazol-5-yl)-7-chloro- quinazoline-2,4(1H,3H)-dione m/z[M + H]+ 313.0 341

4-(methylamino)-1-(pyridin-3-yl)-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 321.0 342

8-chloro-1-(2-chlorophenyl)-4- (methylamino)-7-(trifluoromethyl)-hydroquinazolin-2-one m/z [M + H]+ 388.0 343

8-chloro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 354.04 344

4-((2R)-2-methylpyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 375.1 345

4-((2S)-2-methylpyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 375.1 346

1-phenyl-4-(1,3-thiazolidin-3-yl)-7- (trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 379.1 347

7-chloro-1-(2-chlorophenyl)-4- ((methyl-d3)amino)quinazolin-2(1H)- onem/z [M + H]+ 324.1 348

7-chloro-5-(cyclopropylmethoxy)-4- (methylamino)-1-phenylhydro-quinazolin-2-one m/z [M + H]+ 356.32 349

7-chloro-4-(methylamino)-5-(methyl-ethoxy)-1-phenylhydroquinazolin-2-one m/z [M + H]+ 344.33 350

7-chloro-4-(methylamino)-1-phenyl-5-(2,2,2-trifluoroethoxy)hydroquinazolin- 2-one m/z [M + H]+ 384.31 351

1-(2-bromophenyl)-7-cyclopropyl-4- (methylamino)hydroquinazolin-2-onem/z [M + H]+ 370.26 352

7-cyclopropyl-4-(methylamino)-1-(2- methylphenyl)hydroquinazolin-2-onem/z [M + H]+ 306.33 353

7-chloro-1-(3-cyclopropylphenyl)-4- (methylamino)hydroquinazolin-2-onem/z [M + H]+ 326.32 354

7-chloro-1-(3-difluoromethylphenyl)- quinazoline-2,4(1H,3H)-dione m/z[M + H]+ 323.26 355

7-chloro-1-(3-(difluoromethyl)phenyl)- 4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one m/z [M + H]+ 336.30 356

7-chloro-1-(3-trifluoromethylphenyl)- quinazoline-2,4(1H,3H)-dione m/z[M + H]+ 339.29 357

1-(1H-indazol-5-yl)-7-chloro-4- hydroxy-hydroquinazolin-2-one m/z [M +H]+ 313.0 358

1-(4-chloropyridin-3-yl)-7-(trifluoro- methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M + H]+ 343.0 359

1-(pyridin-3-yl)-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)- dione m/z [M + H]+ 309.00 360

8-chloro-1-(2-chlorophenyl)-7- (trifluoro-methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione-1 m/z [M + H]+ 373.0 361

8-chloro-1-phenyl-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)- dione m/z [M + H]+ 339.0 362

1-(pyridin-3-yl)-7-(trifluoromethyl)-1,3- dihydroquinazoline-2,4-dionem/z [M + H]+ 308.0 363

1-benzothiazol-7-yl-7-(trifluoromethyl)-pyrido[2,3-d]pyrimidine-2,4(1H,3H)- dione m/z [M + H]+ 365.0 364

1-(2-methylpyridin-3-yl)-7-(trifluoro- methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M + H]+ 323.1 365

1-(4-methylpyridin-3-yl)-7-(trifluoro- methyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione m/z [M + H]+ 323.1 366

4-((methyl-d3)amino)-1-phenyl-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 324.1 367

4-((methyl-d3)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 337.2 368

1-(2-bromophenyl)-7-chloro-4- ((methyl-d3)amino)quinazolin-2(1H)- onem/z [M + H]+ 367.0 369

4-((methyl-d3)amino)-1-phenyl-7- (trifluoromethyl)quinazolin-2(1H)-onem/z [M + H]+ 323.2 370

7-chloro-1-(3-chloro(2-pyridyl))-4- (methylamino)hydroquinazolin-2-onem/z [M + H]+ 321.26 371

7-chloro-1-(3-methylpyridin-2-yl))-4- (methylamino)hydroquinazolin-2-onem/z [M + H]+ 301.3 372

7-cyclopropyl-4-(3-hydroxyazetidin-1- yl)-1-phenylhydroquinazolin-2-onem/z [M + H]+ 334.36 373

7-cyclopropyl-4((2-fluoropropyl)- amino)-1-phenylquinazolin-2(1H)-onem/z [M + H]+ 342.35 374

4-((3R)-3-hydroxypyrrolidinyl)-7- cyclopropyl-1-phenylhydroquazolin-2-one m/z [M + H]+ 348.37 375

7-cyclopropyl-1-(o-tolyl)quinazoline- 2,4(1H,3H)-dione m/z [M + H]+293.25 376

4-(methylamino)-1-(4-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+336.1 377

1-(4-chloropyridin-3-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+356.00 378

4-(methylamino)-1-(pyridin-3-yl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 322.10 379

1-(2-chlorophenyl)-4-((methyl-d3)- amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 358.00 380

4-(methylamino)-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+336.1 381

1-benzothiazol-7-yl-4-(methylamino)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 378.0 382

4-(methylamino)-7-(methylpropyl)-1- phenylhydroquinazolin-2-one m/z [M +H]+ 308.2 383

4-amino-5,7-dichloro-1-phenyl- hydroquinazolin-2-one m/z [M + H]+ 306.23384

4-(3-hydroxyazetidin-1-yl)-7-methyl-1-phenylpyrid0[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 309.32 385

7-cyclopropyl-1-phenyl-4-[(2,2,2- trifluoroethyl)amino]hydroquinazolin-2-one m/z [M + H]+ 360.36 386

7-cyclopropyl-1-phenyl-4-pyrrolidin-1- ylhydroquinazolin-2-one m/z [M +H]+ 332.38 387

4-amino-7-chloro-1-phenyl-5-pyrazol- 1-ylhydroquinazolin-2-one m/z [M +H]+ 338.31 388

1-(2-chlorophenyl)-7-(trifluoromethyl)-1,3-dihydropyridino[2,3-d]pyrimidine- 2,4-dione m/z [M + H]+ 342.0 389

1-(2-chlorophenyl)-4-[(2,2,2-trifluoro- inethyl)amo]-7-(trifluoro-methyl)- pyrido[2,3-d]pyrimidin-2(1H)-one m/z[M + H]+ 423.10 390

1-(5-hydroxypyridin-3-yl)-4-(methyl- inamo)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M + H]+338.10 391

1-(2-hydroxypyridin-4-yl)-4-(methyl- amino)-7-(trifluoromethyl)-pyridod]pyrimidin-2(1H)-one m/z [M + H]+ 338.10 392

1-(4-hydroxypyridin-3-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 338.10 393

1-(5-hydroxypyridin-2-yl)-4-(methyl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 338.10 394

7-ethynyl-4-(methylamino)-1-phenyl- hydroquinazolin-2-one m/z [M + H]+276.0 395

4-((3R)-3-hydroxypyrrolidin-1-yl)-1-(2- chlorophenyl)-7-(trifluoromethyphydro-quinazolin-2- one m/z [M + H]+ 410.0 396

4-methoxy-7-methyl-1-phenylpyrido- [2,3-d]pyrimidin-2(1H)-one m/z [M +H]+ 268.12 397

7-methyl-1-phenyl-4-[(2,2,2-trifluoro-ethyl)amino]pyrido[2,3-d]pyrimidin- 2(1H)-one m/z [M + H]+ 335.16 398

4-[(2,2-difluoroethyl)amino]-7-methyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 317.17 399

7-cyclopropyl-4-methoxy-1-phenyl- hydroquinazolin-2-one m/z [M + H]+293.1 400

4-amino-7-cyclopropyl-1-phenylhydro- quinazolin-2-one m/z [M + H]+278.21 401

1-(3-bromophenyl)-7-chloro-4- (methylamino)hydroquinazolin-2-one m/z[M + H]+ 363.97 402

5-(2-aminoethoxy)-7-chloro-4-(methyl-amino)-1-phenylhydroquinazolin-2-one m/z [M + H]+ 345.1 403

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-(methylsulfonyl)ethyl)amino)-2-oxo-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 443.1 404

4-[((1R,2R)-2-fluorocyclopropyl)- amino]-1-(2-chlorophenyl)-7-(trifluoromethoxy)hydroquinazolin-2- one m/z [M + H]+ 414.0. 405

4-methoxy-7-methyl-1-(2-methyl- pyridin-3-yl)quinazolin-2(1H)-one m/z[M + H]+ 336.40 406

5-(difluoromethoxy)-1-(2- chlorophenyl)-7-cyclopropyl-4-(methylamino)hydro-quinazolin-2-one m/z [M + H]+ 392.3. 407

1-(2-chlorophenyl)-7-cyclopropyl-4-{[(fluorocyclopropyl)methyl]amino}-5- methoxyhydroquinazolin-2-one m/z[M + H]+ 414.39 408

1-(2-chlorophenyl)-7-cyclopropyl-4-((oxetan-2-ylmethyl)amino)-2-oxo-1,2- dihydroquinazoline-6-carbonitrilem/z [M + H]+ 407.0 409

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2- dihydroquinazoline-6-carbonitrilem/z [M + H]+ 391.0 410

7-cyclopropyl-5-ethyl-4- (methylamino)-1-(2-methylphenyl)hydroquinazolin-2-one m/z [M + H]+ 334.37. 411

6-chloro-1-(2-chlorophenyl)-7-cyclo- propyl-4-[(cyclopropylmethypamino]-hydroquinazolin-2-one m/z [M + H]+ 400.1. 412

7-bromo-6-chloro-1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)hydroquinazolin- 2-one m/z [M + H]+ 452.9 (major)413

4-[((2S,1R)-2- fluorocyclopropyl)amino]-1-(2-chlorophenyl)-7-cyclopropyl- hydroquinazolin-2-one m/z [M + H]+ 370.0414

4-(methylamino)-7-(methylethyl)-1- phenylpyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 295.1 415

7-cyclopropyl-4-(((cyclopropylmethyl)- amino]-1-((2-(trifluoromethyl)(3-pyridyl)hydroquinazolin-2-one m/z [M + H]+ 399.1 416

1[2-(difluoromethoxy)(3-pyridyl)]-7- cyclopropyl-4-[(cyclopropylmethyl)-amino]hydroquinazolin-2-one m/z [M + H]+ 401.1. 417

6-bromo-1-(2-chlorophenyl)-7-cyclo- propyl-4-(methylamino)hydro-quinazolin-2-one m/z [M + H]+ 404.0 418

1-(2-chlorophenyl)-4-(((1S,2S)-2- fluorocyclopropyl)amino)-7-(trifluoro-methoxy)quinazolin-2(1H)-one m/z [M + H]+ 414.0. 419

2-(3-(7-chloro-4-(methylamino)-2- oxoquinazolin-1(2H)-yl)phenyl)aceticacid m/z [M + H]+ 344.30. 420

5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)hydroquinazolin-2-one m/z [M + H]+ 338.1. 421

1-(2-chloropheny0-4-(pyridin-4-yl- amino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 418.00. 422

1-(2-chlorophenyl)-4-cyclopropoxy-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 382.33 423

1-(2-chlorophenyl)-7-cyclopropyl-4- methoxyhydroquinazolin-2-one m/z[M + H]+ 327.16. 424

44(1S,2R)-2- fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 364.1 425

1-(2-chlorophenyl)-4-((cyclopropyl- methyl)amino)-7-(1,1-difluoroethyl)-quinazolin-2(1H)-one m/z [M + H]+ 390.1 426

1-(2-chlorophenyl)-7-cyclopropyl-4- (methylamino)quinazolin-2(1H)-onem/z [M + H]+ 326.0 427

(S)-4-(pyrrolidin-3-ylamino)-1-(o- tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 389.15 428

(R)-4-(2-(hydroxymethyl)azetidin-1- yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 391.1429

N-methyl-24(2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)ethane-1-sulfonamide m/z [M +H]+ 442.1 430

N-methyl-3-((2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)propane-1-sulfonamide m/z [M +H]+ 456.1 431

N-cyclopropyl-242-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)ethane-1-sulfonamide m/z [M +H]+ 468.1 432

44(1S,2R)-2- fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 379.1433

44(1R,2S)-2- fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 379.1434

N,N-dimethyl-342-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane- 1-sulfonamide m/z [M + H]+ 469.1435

N,N-dimethyl-242-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane- 1-sulfonamide m/z [M + H]+ 455.1436

tert-butyl (R)-3-((2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4- yl)amino)pyrrolidine-1-carboxylate m/z [M + H]+489.2 437

4-((2- (morpholinosulfonyl)ethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin- 2(1H)-one m/z [M + H]+ 497.1 438

(S)-4-(3-(methylamino)pyrrolidin-1-yl)- 1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 403.1 439

N-cyclopropyl-242-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane- 1-sulfonamide m/z [M + H]+ 467.1440

(R)-4-(2-(hydroxymethyl)azetidin-1- yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 390.1 441

4-(3-(hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 390.1442

(R)-4-(2-(methoxymethyl)azetidin-1- yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 404 443

4-((3S,4S)-3,4-dihydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+406.1 444

44(1R,2S)-2- fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 378.1 445

44(1S,2R)-2- fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 378.1 446

3-((2-oxo-1-(o-tolyl)-7-(trifluoro- methyl)-1,2-dihydroquinazolin-4-yl)-amino)propane-1-sulfonamide m/z [M + H]+ 441.1 447

N-methyl-3-((2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane- 1-sulfonamide m/z [M + H]+ 455.1448

2-((2-oxo-1-(o-tolyl)-7-(trifluoro- methyl)-1,2-dihydroquinazolin-4-yl)-amino)ethane-1-sulfonamide m/z [M + H]+ 427.05 449

N-methyl-24(2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane- 1-sulfonamide m/z [M + H]+ 441.1450

(S)-4-(2-(hydroxymethyl)morpholino)- 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 420.1 451

4-(3-methoxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 390.1 452

(4-(4-methyl-3-oxopiperazin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 417.1 453

4-(3-hydroxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 376.1 454

1-(2-oxo-1-(o-tolyl)-7- (trifluoromethyl)-1,2-dihydroquinazolin-4-yl)azetidine-3- carbonitrile m/z [M + H]+ 385.1 455

amino(3-1[1-(2-methylphenyl)-2-oxo-7-(trifluoromethyl)hydroquinazolin-4-yl]- amino-1-propyl)sulfonamide m/z[M + H]+ 456.1 456

amino(2-1[1-(2-methylphenyl)-2-oxo-7-(trifluoromethyl)hydroquinazolin-4-yl]- amino)ethyl)sulfonamide m/z [M +H]+ 442.1 457

(3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)- amino)propane-1-sulfonamide m/z [M +H]+ 433.1 458

3-((1-(2-chlorophenyl)-7-cyclopropyl- 2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropane-1- sulfonamide m/z [M + H]+ 447.0 459

2-((1-(2-chlorophenyl)-7-cyclopropyl- 2-oxo-1,2-dihydroquinazolin-4-yl)-amino)ethane-1-sulfonamide m/z [M + H]+ 419.0 460

2-((1-(2-chlorophenyl)-7-cyclopropyl- 2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylethane-1- sulfonamide m/z [M + H]+ 433.1 461

1-(2-chlorophenyl)-7-cyclopropyl-4-(4- (hydroxymethyl)piperidin-1-yl)-quinazolin-2(1H)-one m/z [M + H]+ 410.1 462

1-(2-chlorophenyl)-7-cyclopropyl-4-(3- hydroxypiperidin-1-yl)quinazolin-2(1H)-one m/z [M + H]+ 396.1 463

1-(2-chlorophenyl)-7-cyclopropyl-4-(3-hydroxyazetidin-1-yl)quinazolin-2(1H)- one m/z [M + H]+ 368.1 464

(3-1[1-(2-chlorophenyl)-7-cyclopropyl- 2-oxohydroquinazolin-4-yl]amino}- propyl) sulfonamide m/z [M + H]+ 448.1 465

(2-1[1-(2-chlorophenyl)-7-cyclopropyl- 2-oxohydroquinazolin-4-yl]amino}- ethyl)sulfonamide m/z [M + H]+ 434.0 466

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-(difluoromethyl)pyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 439.1 467

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-cyclopropylpyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 429.1 468

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-(difluoromethoxy)pyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 455.1 469

1-(2-chlorophenyl)-7-cyclopropyl-4- ((3-methyl-1,2,4-oxadiazol-5-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 394.1 470

1-(2-chlorophenyl)-7-cyclopropyl-4-((oxazol-5-ylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 393.1 471

1-(2-chlorophenyl)-7-cyclopropyl-4- ((isoxazol-3-ylmethyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 393.1 472

1-(2-chlorophenyl)-7-cyclopropyl-4- ((5-methylisoxazol-3-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 393.1 473

1-(2-chlorophenyl)-7-cyclopropyl-4- (( (1-methyl-1H-pyrazol-4-yl)methyl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 406.1 474

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-3-ylamino)quinazolin-2(1H)- one m/z [M + H]+ 379.05 475

1-(2-chlorophenyl)-7-cyclopropyl-4- ((5-methoxypyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 419.1 476

1-(2-chlorophenyl)-7-cyclopropyl-4- ((6-methylpyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 403.1 477

1-(2-chlorophenyl)-7-cyclopropyl-4- ((6-methoxypyridin-3-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 419.1 478

1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-4-ylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 403.1 479

1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-3-ylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 403.1 480

1-(2-chlorophenyl)-7-cyclopropyl-4-((pyridin-2-ylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 403.1 481

1-(2-chlorophenyl)-7-isopropyl-4- (methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 329.1 482

1-(2-chlorophenyl)-7-(difluoromethyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 336.0 483

1-(2-chlorophenyl)-7-isopropyl-4- (methylamino)quinazolin-2(1H)-one m/z[M + H]+ 328.1 484

1-(2-chlorophenyl)-7-cyclopropyl-4- (pyrimidin-5-ylamino)quinazolin-2(1H)-one m/z [M + H]+ 390.05 485

1-(2-chlorophenyl)-7-cyclopropyl-4- (pyridin-3-ylamino)quinazolin-2(1H)-one m/z [M + H]+ 389.05 486

1-(2-chlorophenyl)-7-cyclopropyl-4- (pyridin-4-ylamino)quinazolin-2(1H)-one m/z [M + H]+ 389.05 487

4-((1-(2-chlorophenyl)-7-cyclopropyl- 2-oxo-1,2-dihydroquinazolin-4-yl)amino)picolinonitrile m/z [M + H]+ 414.1 488

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-methoxypyridin-4-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 419.1 489

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-morpholinopyridin-4-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 474.1 490

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-fluoropyridin-4-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 407.0 491

1-(2-chlorophenyl)-4((2-chloropyridin-4-yl)amino)-7-cyclopropylquinazolin- 2(1H)-one m/z [M + H]+ 423.0 492

1-(2-chlorophenyl)-5-methoxy-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 384.1 493

1-(2-chlorophenyl)-4-((cyclopropyl- methyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 394.1 494

5-methoxy-4-(methylamino)-1-phenyl- 7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 350.1 495

(R)-1-(2-chlorophenyl)-7-(trifluoro-methyl)-4-((1,1,1-trifluoropropan-2-yl)- amino)quinazolin-2(1H)-one m/z[M + H]+ 436.0 496

(1,3-trans)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydro-quinazolin-4-yl)amino)-cyclobutane-1- carbonitrile m/z [M + H]+ 419.05497

4-(isopropylamino)-1-phenyl-7- (trifluoromethyl)quinazolin-2(1H)-one m/z[M + H]+ 348.1 498

1-(2-chlorophenyl)-4-(isopropylamino)-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 382.0 499

1-(2-chlorophenyl)-4-(cyclopropyl- amino)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 380.0 500

1-(2-chlorophenyl)-4-(isoxazol-4-yl-amino)-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 406.75 501

1-(2-chlorophenyl)-4((1,3-difluoro-propan-2-yl)amino)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M +H]+ 418.1 502

1-(2-chlorophenyl)-4-(((1R,2S)-2- fluorocyclopropyl)amino)-7-(trifluoro-methyl)quinazolin-2(1H)-one m/z [M + H]+ 398.05 503

1-(2-chlorophenyl)-4-(((1S,2R)-2- fluorocyclopropyl)amino)-7-(trifluoro-methyl)quinazolin-2(1H)-one m/z [M + H]+ 398.1 504

4-((cyclopropylmethyl)amino)-1- phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 360.1 505

7-isopropyl-4-(methylamino)-1-phenyl- quinazolin-2(1H)-one m/z [M + H]+294.2 506

4-((2,2-difluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 382.05 507

4-((1,3-difluoropropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 384.1 508

(R)-4-((1-cyclopropylethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 374.1 509

4-(((1- fluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 378.1 510

4-((((trans)-2-(hydroxymethyl)cyclo- propyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 390.1 511

1-(imidazo[1,2-a]pyridin-5-yl)-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 360.1 512

1-(2-chlorophenyl)-7-cyclopropyl-4- (methylamino)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 327.1 513

7-cyclopropyl-1-(imidazo[1,2- a]pyridin-5-yl)-4-(methylamino)pyrido[2,3-d]-pyrimidin- 2(1H)-one m/z [M + H]+ 333.1 514

7-methoxy-4-(methylamino)-1-phenyl- pyrido[2,3-d]pyrimidin-2(1H)-one m/z[M + H]+ 283.1 515

1-(3-chloropyridin-2-yl)-4-(methyl-amino)-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 355.0 516

4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)- quinazolin-2(1H)-one m/z [M + H]+389.1 517

4-(methylamino)-1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 322.1 518

(S)-1-phenyl-7-(trifluoromethyl)-4- ( ( 1 , 1 ,1-trifluoropropan-2-yl)amino)- quinazolin-2(1H)-one m/z [M + H]+ 402.1519

4-((oxetan-2-ylmethyl)amino)-1- phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 376.1 520

44(1R,2S)-2- fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 364.1 521

4-(((1,2-trans)-2-fluorocyclopropyl)- amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 364.1 522

4(((2,2-difluorocyclopropyl)methyl)-amino)-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+396.1 523

(R)-4-((1-hydroxypropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 364.1 524

4-(oxetan-3-ylamino)-1-phenyl-7- (trifluoromethyl)quinazolin-2(1H)-onem/z [M + H]+ 362.1 525

4-(((1,3-trans)-3-methoxycyclobutyl)-amino)-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+390.1 526

4-((3-methoxypropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 378.1 527

4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 364.1 528

4((3-methoxypropyl)amino)-1-phenyl- 7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 378.1 530

4-((2-(difluoromethoxy)ethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 400.1 531

7-cyclopropyl-4-(methylamino)-1- phenylpyrido[2,3-d]pyrimidin-2(1H)- onem/z [M + H]+ 293.1 532

(R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-to1yl)-7-(trffluoromethyl)- pyrido[2,3-d]pyrimidin-2(1H)-onem/z [M + H]+ 405.00 533

(R)-4-(2-(hydroxymethyl)pyrrolidin-1- yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 405.00534

4-(pyrrolidin-1-yl)-1-(o-tolyl)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 375.2 535

4-(3-(2-hydroxyethyl)pyrrolidin-1-yl)- 1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 418.1 536

(R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+418.1 537

(R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+404.1 538

(S)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+404.1 539

(R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2 (1H)-one m/z [M + H]+404.1 540

4(((3-methoxyisoxazol-5-yl)methyl)-amino)-1-(o-tolyl)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M +H]+ 431.1 541

4-((isoxazol-3-ylmethyl)amino)-5- methoxy-1-phenyl-7-(tri fluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 417.1 542

5-methoxy-4(((3-methoxyisoxazol-5- yl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 447.1 543

5-methoxy-4-((oxazol-4-ylmethyl)- amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 417.1 544

4-((isoxazol-4-ylmethyl)amino)-5- methoxy-1-phenyl-7-(tri fluoromethyl)-elquinazolin-2(1H)-one m/z [M + H]+ 417.1 545

5-methoxy-4-((oxazol-2-ylmethyl)- amino)-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 417.1 546

4-(isobutylamino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 392.15 547

1-(2-chlorophenyl)-7-cyclopropyl-4- ((3,5-dimethylisoxazol-4-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 407.1 548

1-(2-chlorophenyl)-7-cyclopropyl-4- ((3-methylisoxazol-4-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 393.1 549

1-(2-chlorophenyl)-7-cyclopropyl-4- ((5-methylisoxazol-4-yl)amino)quinazolin-2(1H)-one m/z [M + H]+ 393.1 550

1-(2-chlorophenyl)-7-cyclopropyl-4- ((cyclopropylmethyl)(methyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 380.15 551

4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-7-(trifluoromethoxy)-1,2- dihydroquinazoline-6-carbonitrilem/z [M + H]+ 415.1 552

4-((cyclopropylmethyl)amino)-6- methyl-1-(o-tolyl)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 404.1 553

6-methyl-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)- one m/z [M + H]+ 364.1 554

4-((cyclopropylmethyl)amino)-6- methyl-1-phenyl-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M + H]+ 390.1 555

6-bromo-4- ((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)-quinazolin- 2(1H)-one m/z [M + H]+ 468.0,470.0 556

6-bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)- one m/z [M + H]+ 430.0, 428.0 557

6-bromo-4- ((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 456.1, 454.1 558

44(1R,2S)-2- fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+ 394.05559

44(1S,2R)-2- fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+ 394.05560

4-amino-5-methoxy-1-phenyl-7- (trifluoromethyl)quinazolin-2(1H)-one m/z[M + H]+ 336.0 561

4-(((trans)-2-fluorocyclopropyl)amino)- 5-methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 394.05 562

7-cyclopropyl-4- (cyclopropylmethylamino)-1-(3-(trifluoromethyl)pyrazin-2-yl)- quinazolin-2(1H)-one m/z [M + H]+ 402.1563

7-cyclopropyl-4-(methylamino)-1-(3- (trifluoromethyl)pyrazin-2-yl)quinazolin-2(1H)-one m/z [M + H]+ 362.1 564

4-(((trans)-2- hydroxycyclobutyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+ 406.1565

(S)-4-((2-hydroxypropyl)amino)-5- methoxy-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 394.1 566

5-methoxy-4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 394.1 567

4-((2-hydroxyethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one m/z [M + H]+ 380.1 568

4-((cyclopropylmethyl)amino)-5- methoxy-1-phenyl-7-(tri fluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 390.1 569

5-fluoro-4-((trans-2-fluorocyclopropyl)-amino)-1-phenyl-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+382.1 570

(R)-6-chloro-1-(2-chlorophenyl)-7- cyclopropyl-4((2-hydroxypropyl)-amino)-quinazolin-2(1H)-one m/z [M + H]+ 405.05 571

(S)-6-chloro-1-(2-chlorophenyl)-7- cyclopropyl-4((2-hydroxypropyl)-amino)-quinazolin-2(1H)-one m/z [M + H]+ 405.1 572

1-(2-chlorophenyl)-7-cyclopropyl-4- ((3-methoxypropyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 384.1 573

1-(2-chlorophenyl)-7-cyclopropyl-4- ((3-hydroxypropyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 370.1 574

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-methoxyethyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 370.1 575

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-hydroxyethyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 356.1 576

1-(2-chlorophenyl)-7-cyclopropyl-4- (((S)-1-hydroxypropan-2-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 370.1 577

1-(2-chlorophenyl)-7-cyclopropyl-4- (((R)-1-hydroxypropan-2-yl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 370.1 578

1-(2-chlorophenyl)-7-cyclopropyl-4-((1-methylcyclobutyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 380.15 579

4-amino-6-chloro-1-(2-chlorophenyl)-7- cyclopropylquinazolin-2(1H)-onem/z [M + H]+ 347.0 580

4-amino-7-cyclopropyl-1-(2-(trifluoro-methyl)pyridin-3-yl)quinazolin-2(1H)- one m/z [M + H]+ 347.0 581

4-amino-1-(2-chlorophenyl)-7- (trifluoromethoxy)quinazolin-2(1H)- onem/z [M + H]+ 356.0 582

1-(2-chlorophenyl)-7-cyclopropyl-4-(((trans)-2-hydroxycyclobutyl)amino)- quinazolin-2(1H)-one m/z [M + H]+382.1 583

6-bromo-1-(2-chlorophenyl)-7- cyclopropyl-4-(isoxazol-4-ylamino)-quinazolin-2(1H)-one m/z [M + H]+ 458.0 584

1-(2-chlorophenyl)-4-(((trans)-2- hydroxycyclobutypamino)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 426.1 585

6-bromo-1-(2-chlorophenyl)-7- cyclopropyl-4-((cyclopropylmethyl)-amino)-quinazolin-2(1H)-one m/z [M + H]+ 445.0 586

6-chloro-1-(2-chlorophenyl)-7- cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 360.0 587

6-chloro-1-(2-chlorophenyl)-4- ((cyclopropylmethyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 428.0 588

6-chloro-1-(2-chlorophenyl)-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 388.0 589

7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 439.9 590

7-bromo-6-chloro-1-(2-chlorophenyl)- 4-(methylamino)quinazolin-2(1H)-onem/z [M + H]+ 399.9 591

7-cyclopropyl-4-(methylamino)-1-(2- (trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one m/z [M + H]+ 361.1 592

7-cyclopropyl-1-(2-(difluoro- methoxy)pyridin-3-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 359.1 593

4-((cyclopropylmethyl)amino)-1- Hmi dazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 416.1 594

1-(imidazo[1,2-a]pyridin-5-yl)-4- (methylamino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M + H]+ 376.1 595

1-(2-chlorophenyl)-4-(isoxazol-4- ylamino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M + H]+ 423.0 596

7-cyclopropyl-4-(isothiazol-4-ylamino)- 1-(o-tolyl)quinazolin-2(1H)-onem/z [M + H]+ 375.1 597

7-cyclopropyl-4-(isoxazol-4-ylamino)- 1-(o-tolyl)quinazolin-2(1H)-onem/z [M + H]+ 359.1 598

1-(2-chlorophenyl)-4-(((1S,2R)-2- fluorocyclopropyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 414.05 599

1-(2-chlorophenyl)-4-(((1R,2S)-2- fluorocyclopropyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 414.05 600

1-(2-chlorophenyl)-4-(isothiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M +H]+ 424.0 601

4-(methylamino)-1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 322.1 602

4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin- 5-yl)quinazolin-2(1H)-one m/z[M + H]+ 396.2 603

7-cyclopropyl-4-((cyclopropylmethyl)-amino)-1-(imidazo[1,2-a]pyridin-5-yl)- quinazolin-2(1H)-one m/z [M + H]+372.15 604

4-(methylamino)-1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 322.1 605

4-(cyclopropylamino)-7-(1,1- difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)-quinazolin-2(1H)-one m/z [M + H]+ 382.2 606

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-methoxyethyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 370.1 607

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-hydroxyethyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 356.1 608

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 366.1 609

1-(2-chlorophenyl)-7-cyclopropyl-4- (cyclopropylamino)quinazolin-2(1H)-one m/z [M + H]+ 352.1 610

7-(1,1-difluoroethyl)-1-(imidazo[1,2- alpyridin-5-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 356.1 611

1-(2-chlorophenyl)-4((2- hydroxyethyl)-amino)-7-(trifluoromethoxy)quinazolin-2(1H)- one m/z [M + H]+ 400.1 612

1-(2-chlorophenyl)-7-(1,1- dffluoroethyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-quinazolin- 2(1H)-one m/z [M + H]+ 406.1 613

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-((2-methoxyethyl)amino)quinazolin-2(1H)- one m/z [M + H]+ 394.05 614

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-((2-hydroxyethyl)amino)quinazolin-2(1H)- one m/z [M + H]+ 380.05 615

1-(2-chlorophenyl)-4-(cyclopropyl-amino)-7-(1,1-difluoroethyl)quinazolin- 2(1H)-one m/z [M + H]+ 376.1 616

1-(2-chlorophenyl)-4-(((trans)-3- hydroxycyclobutyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)- one m/z [M + H]+ 426.1 617

1-(2-chlorophenyl)-4-((2- methoxyethyl)-amino)-7-(trifluoromethoxy)quinazolin-2(1H)- one m/z [M + H]+ 414.0 618

1-(2-chlorophenyl)-4-((cyclopropyl- methyl)amino)-7-(trifluoromethoxy)-quinazolin-2(1H)-one m/z [M + H]+ 410.0 619

1-(2-chlorophenyl)-4-(cyclopropyl-Famino)-7-(trifluoromethoxy)quinazolin- 2(1H)-one m/z [M + H]+ 396.0 620

1-(2-chlorophenyl)-7-(trifluoromethyl)-4((2-(trifluoromethyl)pyridin-4-yl)-amino)-pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 486.05 621

7-ethyl-4-(methylamino)-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 282.15 622

1-(2-chlorophenyl)-4-((2-methoxy- pyridin-4-yl)amino)-7-(trifluoromethyl)-pyrido-[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 448.1623

1-(2-chlorophenyl)-4-((2- methylpyridin-4-yl)amino)-7-(trifluoromethyl)-pyrido[2,3- d]pyrimidin-2(1H)-one 624

7-ethyl-1-(2-fluorophenyl)-4-(methyl-amino)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 299.1 625

1-(2-chlorophenyl)-7-ethyl-4-(methyl-amino)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 315.1 626

7-ethyl-4-(methylamino)-1-(o-tolyl)- pyrido[2,3-d]pyrimidin-2(1H)-onem/z [M + H]+ 295.15 627

7-ethyl-4-(methylamino)-1-phenyl- pyrido[2,3-d]pyrimidin-2(1H)-one m/z[M + H]+ 281.2 628

1-(2-chlorophenyl)-445-methyl- isoxazol-3-yl)amino)-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 422.05 629

1-(2-chlorophenyl)-4-(isoxazol-4-yl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 408.0 630

1-(2-chlorophenyl)-4-((1-methyl-1H- pyrazol-4-yflamino)-7-(trifluoromethyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 421.0631

1-(2-chlorophenyl)-4-((1-methyl-1H- pyrazol-3-yflamino)-7-(trifluoro-methyl)pyrido-[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 421.0 632

1-(2-chlorophenyl)-4-((1-methyl-1H- imidazol-4-yl)amino)-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 421.0 633

1-(2-chlorophenyl)-4-((1-methyl-1H- pyrazol-5-yflamino)-7-(trifluoromethyl)-pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 421.0634

1-(2-chlorophenyl)-4-(pyridin-3-yl-amino)-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 418.0 635

1-(2-fluorophenyl)-4-(methylamino)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 339.1 636

1-(2-bromophenyl)-4-(methylamino)-7- (trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 401.0, 399.0 637

(R)-4-(3-hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3- d]-pyrimidin-2(1H)-one m/z [M +H]+ 377.1 638

4-amino-1-(2-chlorophenyl)-7- cyclopropylquinazolin-2(1H)-one m/z [M +H]+ 312.00 639

1-(2-chlorophenyl)-7-cyclopropyl-4- (isopropylamino)quinazolin-2(1H)-onem/z [M + H]+ 354.20 640

1-(2-chlorophenyl)-7-cyclopropyl-4-(((lS,2R)-2-fluorocyclopropyl)amino)- quinazolin-2(1H)-one m/z [M + H]+370.00 641

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)- one m/z [M + H]+ 379.00 642

1-(2-chlorophenyl)-7-cyclopropyl-4- (isothiazol-4-ylamino)quinazolin-one m/z [M + H]+ 395.00 643

1-(2-chlorophenyl)-7-cyclopropyl-4- ((2-(trifluoromethyl)pyridin-4-yl)amino)-quinazolin-2(1H))-one m/z [M + H]+ 457.00 644

7-cyclopropyl-1-(imidazo[1,2- a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 332.00 645

7-cyclopropyl-4-((cyclopropylmethyl)- amino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one m/z [M + H]+ 334.20 646

7-cyclopropyl-4-(methylamino)-1-(3- methylpyrazin-2-yl)quinazolin-2(1H)-one m/z [M + H]+ 308.20 647

7-cyclopropyl-4-((cyclopropylmethyl)- amino)-1-(3-methylpyrazin-2-yl)-quinazolin-2(1H)-one m/z [M + H]+ 348.20 648

7-cyclopropyl-1-(imidazo[1,2- alpyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 332.00 649

5-methoxy-4-(methylamino)-7- (trifluoromethyl)-1-(2-(trifluoromethyl)-pyridin-3- yl)quinazolin-2(1H)-one m/z [M + H]+ 419.00650

4-((cyclopropylmethyl)amino)-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoro-methyl)-pyridin-3-yl)quinazolin-2(1H)- one m/z [M + H]+ 447.00 651

4-amino-7-chloro-1-(imidazo[1,2-a]- pyridin-7-yl)quinazolin-2(1H)-onem/z [M + H]+ 312.0 652

7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)- one m/z [M + H]+ 326.0 653

7-chloro-4-((2,2-difluoroethyl)amino)- 1-(imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-one m/z [M + H]+ 376.0 654

7-chloro-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)- one m/z [M + H]+ 326.0 655

1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethoxy)quinazolin-2(1H)- one m/z [M + H]+ 370.1 656

4-amino-1-(2-chlorophenyl)-7-(1,1- difluoroethyl)quinazolin-2(1H)-onem/z [M + H]+ 336.1 657

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-one m/z [M + H]+ 403.0 658

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 350.1 659

1-(3-chloropyridin-2-yl)-7-ethyl-4- (methylamino)quinazolin-2(1H)-onem/z [M + H]+ 315.0 660

4-amino-1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazolin-2(1H)-one m/z [M + H]+ 337.0. 661

1-(3-chloropyridin-2-yl)-7-(1,1- difluoroethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 351.0 662

4-amino-7-(1,1-difluoroethyl)-1- (imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-one m/z [M + H]+ 342.1 663

7-(1,1-difluoroethyl)-1-(imidazo[1,2- a]pyridin-7-yl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 356.0 664

1-(2-chlorophenyl)-7-cyclopropyl-4- ((cyclopropylmethyl)amino)-6-methoxyquinazolin-2(1H)-one m/z [M + H]+ 396.2 665

6-bromo-1-(2-chlorophenyl)-7- cyclopropyl-4-(((1S,2R)-2-fluorocyclo-propyl)amino)quinazolin-2(1H)-one m/z [M + H]+ 448.0/450.0 666

1-(2-chlorophenyl)-7-cyclopropyl-4-(((lS,2R)-2-fluorocyclopropyl)amino)- 2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M + H]+ 395.0 667

1-(2-chlorophenyl)-7-cyclopropyl-4-(((trans)-2-fluorocyclopropyl)amino)-2- oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M + H]+ 395.0 668

4-amino-1-(2-chlorophenyl)-7- cyclopropyl-2-oxo-1,2-dihydro-quinazoline-6-carbonitri1e m/z [M + H]+ 337.0 669

1-(2-chlorophenyl)-7-cyclopropyl-4- (hydroxymethyl)cyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 421.0 670

1-(2-chlorophenyl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydro- quinazoline-6-carbonitrile m/z [M +H]+ 379.0 671

1-(2-chlorophenyl)-4-((cyclopropyl- methyl)amino)-2-oxo-7-(trifluoro-methyl)-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 419.0 672

1-(2-chlorophenyl)-7-cyclopropyl-6-fluoro-4-(methylamino)quinazolin-2(1H)- one m/z [M + H]+ 344.0 673

7-bromo-1-(2-chlorophenyl)-6-fluoro-4- (methylamino)quinazolin-2(1H)-onem/z [M + H]+ 381.9/384.0. 674

1-(2-chlorophenyl)-7-cyclopropyl-4- ((cyclopropylmethyl)amino)-6-fluoro-quinazolin-2(1H)-one m/z [M + H]+ 384.0 675

1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)-2-oxo-1,2- dihydro-quinazoline-6-carbonitrilem/z [M + H]+ 410.1 676

6-bromo-1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 428.0/430.0 677

6-bromo-1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazolin- 2(1H)-one m/z [M + H]+ 472.0/474.0678

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile m/z [M + H]+ 375.0 679

1-(2-chlorophenyl)-4-((cyclopropyl-methyl)amino)-7-(1,1-difluoroethyl)-2- oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M + H]+ 415.0 680

7-cyclopropyl-4-(methylamino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 331.2681

7-cyclopropyl-4-((cyclopropylmethyl)-amino)-2-oxo-1-(o-tolyl)-1,2-dihydro- quinazoline-6-carbonitrile m/z[M + H]+ 371.2 682

1-(2-chlorophenyl)-7-cyclopropyl-4- (methylamino)-6-(methylthio)-quinazolin-2(1H)-one m/z [M + H]+ 372.0 683

1-(2-chlorophenyl)-7-cyclopropyl-4- ((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-one m/z [M + H]+ 412.0 684

6-bromo-4- ((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)- one m/z [M + H]+ 438.0/440.0 685

6-bromo-4-((cyclopropylmethyl)- (methyl)amino)-1-phenyl-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 452.0/454.0 686

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2- dihydropyrido[2,3-d]pyrimidine-6-carbonitrile m/z [M + H]+ 392.1 687

1-(2-chlorophenyl)-7-cyclopropyl-4-(((lS,2R)-2-fluorocyclopropyl)amino)- 2-oxo-1,2-dihydropyrido[2,3-4pyrimidine-6-carbonitrile m/z [M + H]+ 396.0 688

7-chloro-4-((2,2-difluoroethyl)amino)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)- one m/z [M + H]+ 380.35 689

7-chloro-5-fluoro-4-(((lr,3r)-3- methoxy-cyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M + H]+ 400.33 690

7-chloro-1-(2-chlorophenyl)-5- methoxy-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 350.2 691

5-methoxy-4-(methylamino)-1-(o- tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 364.19 692

5-methoxy-4-(methylamino)-1-phenyl- 7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 351.3 693

1-(2-chloro-6-fluorophenyl)-4- (methylamino)-7-(trifluoromethyl)pyrido[2,3-d]- 0pyrimidin-2(1H)-one m/z [M + H]+ 373.2694

7-cyclopropyl-4-(methylamino)-1-(2- methylpyridin-3-yl)quinazolin-2(1H)one m/z [M + H]+ 307.22 695

1-(2-chlorophenyl)-4-(3-hydroxy-3- methylpyrrolidin-1-yl)-7-(trifluoro-methyl) pyrido[2,3-d]pyrimidin-2(1H)- one, single unknown enantiomer m/z[M + H]+ 425.1 696

1-benzyl-4-(methylamino)-7-(trifluoro-methyl)pyrido[2,3-d]pyrimidin-2(1H)- one m/z [M + H]+ 335.3 697

1-(2-chlorophenyl)-4-(((trans)-2- hydroxycyclobutyl)amino)-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one, single unknown enantiomer/atropisomer m/z [M + H]+ 411.3 698

1-(2-chlorophenyl)-4-(((trans)-2- hydroxycyclobutypamino)-7-(trifluoro-methyl)-pyrido[2,3-d]pyrimidin-2(1H)- one, single unknown enantiomer/atropisomer m/z [M + H]+ 411.3 699

4-amino-1-(2-bromophenyl)-7- cyclopropylquinazolin-2(1H)-one m/z [M +H]+ 356.1 700

1-(2-chlorophenyl)-7-cyclopropyl-5- methoxy-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 356.35 701

4-amino-1-(2-chlorophenyl)-7- cyclopropyl-5-methoxyquinazolin- 2(1H)-onem/z [M + H]+ 342.31 702

7-cyclopropyl-5-methoxy-4- (methylamino)-1-(o-tolyl)quinazolin-2(1H)-one m/z [M + H]+ 366.44 703

4-amino-7-cyclopropyl-5-methoxy-1- (o-tolyl)quinazolin-2(1H)-one m/z[M + H]+ 322.36 704

7-cyclopropyl-5-methoxy-4-(methyl- amino)-1-(pyridin-3-yl)quinazolin-2(1H)-one m/z [M + H]+ 323.36 705

4-amino-7-cyclopropyl-5-methoxy-1- (pyridin-3-yl) quinazolin-2(1H)-onem/z [M + H]+ 309.36 706

7-cyclopropyl-4-(pyridin-4-ylamino)-1- (o-tolyl)quinazolin-2(1H)-one m/z[M + H]+ 369.39 707

1-(2-chlorophenyl)-4-(thiazol-4- ylamino)-7-(trifluoromethyl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 424.2 708

1-(2-chlorophenyl)-4-((isoxazol-4-yl- methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 422.3 709

1-(2-chlorophenyl)-4-((isoxazol-3-yl- methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 422.3 710

1-(2-chlorophenyl)-4-((isoxazol-5-yl- methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one m/z [M + H]+ 422.2 711

1-(2-chlorophenyl)-4(((1-methyl-1H- pyrazol-5-yl)methyl)amino)-7-(trifluoro-methyl)pyrido[2,3- d]pyrimidin-2(1H)-one m/z [M + H]+ 435.27712

2-chlorophenyl)-4(((1-methyl-1H- imidazol-4-yl)methyl)amino)-7-(trifluoro-methyl)-pyrido[2,3-d]- pyrimidin-2(1H)-one m/z [M + H]+435.27 713

cyclopropyl-4-(methylamino)-1- (pyrazin-2-yl)quinazolin-2(1H)-one m/z[M + H]+ 294.4 714

7-cyclopropyl-4-(methylamino)-1- (pyrimidin-5-yl)quinazolin-2(1H)-onem/z [M + H]+ 294.33 715

4-amino-1-(3-chloropyridin-2-yl)-7- cyclopropylquinazolin-2(1H)-one m/z[M + H]+ 313.3 716

4-amino-7-cyclopropyl-1-(pyrazin-2- yl)-quinazolin-2(1H)-one m/z [M +H]+ 280.4 717

4-amino-7-cyclopropyl-1-(pyrimidin-5- yl)quinazolin-2(1H)-one m/z [M +H]+ 280.26 718

4-((trans-2-hydroxycyclobutyl) amino)- 1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one m/z [M + H]+ 376.36 719

1-(2-bromophenyl)-7-cyclopropyl-4- (methylamino)quinazolin-2(1H)-one, asingle atropisomer m/z [M + H]+ 370.3 720

1-(2-chlorophenyl)-7-cyclopropyl-4- (isopropylamino)-5-methoxyquinazolin-2(1H)-one m/z [M + H]+ 384.4 721

1-(2-chlorophenyl)-7-cyclopropyl-4- (cyclopropylamino)-5-methoxy-quinazolin-2(1H)-one m/z [M + H]+ 382.35 722

1-(2-chlorophenyl)-7-cyclopropyl-4- ( ( (1S,2R)-2-fluorocyclopropyl)amino)- 5-methoxyquinazolin-2(1H)-one m/z [M + H]+ 400.33 723

1-(2-chlorophenyl)-7-cyclopropyl-4- ((cyclopropylmethyl)amino)-5-methoxy-quinazolin-2(1H)-one m/z [M + H]+ 396.4 724

1-(2-chlorophenyl)-7-cyclopropyl-4- (((2,2-difluorocyclopropyl)methyl)-amino)-5-methoxyquinazolin-2(1H)- one m/z [M + H]+ 432.4 725

1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 726 726

1-(2-chloropyridin-3-yl)-7-cyclopropyl- 4-methoxyquinazolin-2(1H)-onem/z [M + H]+ 328.3 727

1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazolin- 2(1H)-one m/z [M + H]+ 357.37 728

1-(2-chlorophenyl)-4-(((1S,2S)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 398.3 729

1-(2-chlorophenyl)-4-(((1S,2S)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 398.3 730

1-(2-chlorophenyl)-4-(((1R,2R)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 398.3 731

1-(2-chlorophenyl)-4-(((1R,2R)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 398.3 732

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)- quinazolin-2(1H)-one, singleunknown enantiomer/atropisomer m/z [M + H]+ 370.34 733

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)- quinazolin-2(1H)-one, singleunknown enantiomer/atropisomer m/z [M + H]+ 370.34 734

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)- quinazolin-2(1H)-one, singleunknown enantiomer/atropisomer m/z [M + H]+ 370.34 735

1-(2-chloropyridin-3-yl)-7-cyclopropyl- 4-((cyclopropylmethyl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 367.4 736

1-(2-chloropyridin-3-yl)-7-cyclopropyl- 4-(((lS,2R)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-one m/z [M + H]+ 371.3 737

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(((1R,2R)-2-hydroxycyclobutyl)-aminolquinazolin- 2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 406.37 738

1-(2-chlorophenyl)-7-(1,1- difluoroethyl)-4-(((1R,2R)-2-hydroxycyclobutyl)-aminolquinazolin- 2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 406.37 739

1-(2-chlorophenyl)-7-(1,1- difluoro ethyl)-4-(((1 S,2S )-2-hydroxycyclobutyl)-aminolquinazolin- 2(1H)-one, single unknownenantiomer/atropisomer m/z [M + H]+ 406.37 740

1-(2-chlorophenyl)-4-(((1R,2R)-2- fluorocyclopropyllamino)-7-(trifluoromethoxy)quinazolin-2(1H)- one, single unknown enantiomer m/z[M + H]+ 414.3 741

1-(2-chlorophenyl)-4-(((1 S,2S)-2- fluorocyclopropyllamino)-7-(trifluoromethoxy)quinazolin-2(1H)- one, single unknown enantiomer m/z[M + H]+ 414.3 742

1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydro- quinazoline-6-carbonitrile m/z [M +H]+ 352.4 743

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-hydroxycyclobutyl)amino)- 2-oxo-1,2-dihydroquinazoline-6-carbonitrile, single unknown enantiomer/atropisomer m/z [M + H]+ 407.47744

1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-4-((2-(trifluoromethyl)pyridin-4-yl)-amino)-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 482.5 745

1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-4-(thiazol-5-ylamino)-1,2-dihydro- quinazoline-6-carbonitrile m/z[M + H]+ 420.1 746

1-(2-chlorophenyl)-7-cyclopropyl-4- ((1-methyl-1H-pyrazol-5-yl)amino)-2-oxo-1,2-dihydroquinazoline-6- carbonitrile m/z [M + H]+ 417.36 747

1-(2-chlorophenyl)-7-cyclopropyl-4- ((isoxazol-5-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M + H]+ 418.35 748

1-(2-chlorophenyl)-7-cyclopropyl-4- ((isoxazol-3-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile m/z [M + H]+ 418.3 749

1-(2-chlorophenyl)-7-cyclopropyl-4- (((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxo-1,2- dihydroquinazoline-6-carbonitrile m/z [M +H]+ 431.38 750

1-(2-chlorophenyl)-7-cyclopropyl-6- methyl-4-(methylamino) quinazolin-2(1H)-one m/z [M + H]+ 340.34 751

1-(2-chlorophenyl)-6-methyl-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one m/z [M + H]+ 368.4 752

1-(2-chlorophenyl)-7-cyclopropyl-6- (difluoromethyl)-4-(methylamino)-quinazolin-2(1H)-one m/z [M + H]+ 376.4 753

1-(2-chlorophenyl)-6-(difluoromethyl)-4-(methylamino)-7-(trifluoromethyl)- quinazolin-2(1H)-one m/z [M + H]+404.4 754

6-bromo-1-(2-chloropyridin-3-yl)-7- cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 405.2 755

6-bromo-7-cyclopropyl-4-(methyl- amino)-1-(2-(trifluoromethyl)pyridin-3-yl)-quinazolin-2(1H)-one m/z [M + H]+ 439.4 756

1-(2-bromophenyl)-7-cyclopropyl-4- (methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitri1e, single unknown atropisomer m/z [M + H]+395.41 757

1-(2-bromophenyl)-7-cyclopropyl-4- (methylamino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrile, single unknown atropisomer m/z [M + H]+395.41 758

7-cyclopropyl-1-(2-cyclopropylphenyl)-4-(methylamino)-2-oxo-1,2-dihydro- quinazoline-6-carbonitrile m/z [M +H]+ 357.40 759

7-cyclopropyl-4-(methylamino)-2-oxo- 1-(2-(trifluoromethyl)phenyl)-1,2-dihydro-quinazoline-6-carbonitrile m/z [M + H]+ 385.44 760

44(1R,2R)-2-fluorocyclopropyl)- amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one, single unknown enantiomer m/z[M + H]+ 394.4 761

44(1S,2S)-2- fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin- 2(1H)-one, single unknownenantiomer m/z [M + H]+ 394.4 762

2-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4- yl)amino)-N,N-dimethylethanesulfonamide m/z [M + H]+ 454.19 763

3-((1-(2-chlorophenyl)-2-oxo-7- (trifluoromethyl)-1,2-dihydropyrido[2,3-d]-pyrimidin-4- yl)amino)-N-methylpropanamide m/z [M +H]+ 426.4. 764

7-cyclopropyl-4-((2-((2- ethyl)amino)-1-(2-methylpyridin-3-yl)-quinazolin-2(1H)-one m/z [M + H]+ 362.52 765

2((7-cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4- yl)-amino)-N,N-dimethylethane-1-sulfonamide m/z [M + H]+ 428.49 766

347-cyclopropyl-1-(2-methylpyridin- 3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)-amino)-N-methylpropanamide m/z [M + H]+ 378.47 767

7-cyclopropyl-1-(2-methylpyridin-3- yl)-443-morpholinopropyflamino)-quinazolin-2(1H)-one m/z [M + H]+ 420.31 768

4-(methylamino)-7-(trifluoromethyl)-1- (2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 390.4 769

1-(2-chloropyridin-3-yl)-4- (methylamino)-7-(trifluoromethyl)-pyrido[2,3-d]-pyrimidin-2(1H)-one m/z [M + H]+ 356.3 770

1-(2-chlorophenyl)-4-(((1S,2R)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one, single unknownenantiomer m/z [M + H]+ 399.4. 771

1-(2-chlorophenyl)-4-(((1R,2S)-2- fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3- d]pyrimidin-2(1H)-one, single unknownenantiomer m/z [M + H]+ 399.4 772

(R)-1-(2-bromophenyl)-7-chloro-4-(3- hydroxypyrrolidin-1-yl)quinazolin-2(1H)-one m/z [M + H]+ 420.0, 422.0 773

1-((1H-imidazol-4-yl)methyl)-7- cyclopropyl-4-(methylamino)quinazolin-2(1H)-one m/z [M + H]+ 294.4 774

(S)-1-(1-(1H-imidazol-4-yl)ethyl)-4- (methylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one, Single unknown enantiomer m/z [M + H]+ 338.3. 775

(R)-1-(1-(1H-imidazol-4-yl)ethyl)-4- (methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one, single unknown enantiomer m/z[M + H]+ 338.3 776

1-(2-chlorophenyl)-7-cyclopropyl-4- (methylamino)-6-(methylthio)-quinazolin-2(1H)-one m/z [M + H]+ 324.35

Additional compounds of Formula (I) that are contemplated are disclosedin Table 2 below:

TABLE 2 Structure Name

7-chloro-4-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one

7-chloro-1-phenyl-4-((pyridin-2-ylmethyl)amino)-quinazolin- 2(1H)-one

7-chloro-1-phenyl-4-((pyridin-3-ylmethyl)amino-)quinazolin- 2(1H)-one

7-chloro-1-phenyl-4-((pyridin-4-ylmethyl)amino)-quinazolin- 2(1H)-one

7-chloro-4-(methyl(pyridin-2-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(methyl(pyridin-3-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one

7-chloro-4-((methylamino)methyl)-1-phenylquinazolin-2(1H)-one

7-chloro-4-cyclopropyl-1-phenylquinazolin-2(1H)-one

7-chloro-4-((dimethylamino)methyl)-1-phenylquinazolin-2(1H)- one

2-(7-chloro-2-oxo-1-phenyl-1,2-dihydroquinazolin-4-yl)acetamide

7-chloro-4-(3-hydroxypropyl)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(2-(dimethylamino)ethyl)-1-phenylquinazolin-2(1H)- one

7-chloro-4-(2-(methylamino)ethyl)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(1H-imidazol-2-yl)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(1H-imidazol-5-yl)-1-phenylquinazolin-2(1H)-one

7-chloro-1-phenyl-4-(thiazol-5-yl)quinazolin-2(1H)-one

7-chloro-1-phenyl-4-(thiazol-4-yl)quinazolin-2(1H)-one

7-chloro-4-(isothiazol-4-yl)-1-phenylquinazolin-2(1H)-one

7-chloro-1-phenyl-4-(thiazol-2-yl)quinazolin-2(1H)-one

7-chloro-4-(methyl(pyridin-4-ylmethyl)amino)-1-phenylquinazolin-2(1H)-one

4-amino-7-chloro-1-phenyl-5-(1H-pyrazol-3-yl)quinazolin-2(1H)- one

7-chloro-1-phenyl-5-(pyridin-4-yl)quinazolin-2(1H)-one

4-amino-7-chloro-5-(5-oxopyrrolidin-3-yl)-1-phenylquinazolin- 2(1H)-one

4-amino-7-chloro-1-phenyl-5-(4H-1,2,4-triazol-4-yl)quinazolin- 2(1H)-one

4-amino-7-chloro-1-phenyl-5-(pyridin-4-yl)quinazolin-2(1H)-one

4-amino-7-chloro-5-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin- 2(1H)-one

4-amino-7-chloro-5-morpholino-1-phenylquinazolin-2(1H)-one

4-amino-7-chloro-5-cyclopropyl-1-phenylquinazolin-2(1H)-one

4-amino-7-chloro-1-phenyl-5-(1H-pyrazol-1-yl)quinazolin-2(1H)- one

5-(4-amino-7-chloro-2-oxo-l-phenyl-1,2-dihydroquinazolin-5-yl)oxazolidin-2-one

7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-5-carbonitrile

7-chloro-4-(methylamino)-5-(2-(methylamino)ethoxy)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-6-carboxamide

7-chloro-4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-5-carboxamide

4-amino-7-chloro-5-(2-morpholinoethoxy)-1-phenylquinazolin- 2(1H)-one

3-methyl-8-(methylamino)-5-phenylpyrimido[5,4-c]pyridazin- 6(5H)-one

7-methyl-4-(methylamino)-1-phenylpteridin-2(1H)-one

7-methyl-4-(methylamino)-1-phenylpyrimido 2(1H)-one

4-(dimethylamino)-7-(1-methyl-1H-imidazol-4-yl)-1-phenyl-quinazolin-2(1H)-one

(S)-4-(dimethylamino)-7-(3-hydroxypyrrolidin-1-yl)-1-phenyl-quinazolin-2(1H)-one

4-(dimethylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-7- carboxamide

7-(difluoromethyl)-4-(dimethylamino)-1-phenylquinazolin-2(1H)- one

4-(dimethylamino)-1-phenyl-7-(tetrahydrofuran-2-yl)quinazolin- 2(1H)-one

7-cyclopentyl-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one

4-(dimethylamino)-1-phenyl-7-(trifluoromethoxy)quinazolin- 2(1H)-one

4-(dimethylamino)-7-(2-hydroxypropan-2-yl)-1-phenylquinazolin- 2(1H)-one

4-(dimethylamino)-7-(2-oxoazetidin-1-yl)-1-phenylquinazolin- 2(1H)-one

4-(dimethylamino)-7-(2-oxopyrrolidin-1-yl)-1-phenylquinazolin- 2(1H)-one

4-(dimethylamino)-8-fluoro-7-methyl-1-phenylquinazolin-2(1H)- one

7-(tert-butyl)-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one

4-(dimethylamino)-7-isopropyl-1-phenylquinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(4-oxo-1,4-dihydropyridin-3-yl)quinazolin-2(1H)-one

6-chloro-1-(methylamino)-4-(2-oxo-1,2-dihydropyridin-3-yl)isoquinolin-3(4H)-one

7-chloro-4-(methylamino)-1-(6-oxo-1,6-dihydropyridin-3-yl)quinazolin-2(1H)-one

7-chloro-1-(4-hydroxypyrimidin-2-yl)-4-(methylamino)quinazolin-2(1H)-one

7-chloro-1-(5-hydroxypyridin-3-yl)-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(2-hydroxypyridin-4-yl)-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(6-hydroxypyridin-2-yl)-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(3-(methoxymethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one

1-(3-(aminomethyl)phenyl)-7-chloro-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(4-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)- one

2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)- yl)benzonitrile

7-chloro-1-(2-fluoro-3-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-one

1-(3-aminophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)- one

2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)-cyclopropane-1-carbonitrile

2-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)-cyclobutane-1-carbonitrile

4-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)-cyclohexane-1-carbonitrile

7-chloro-1-cyclohexyl-4-(methylamino)quinazolin-2(1H)-one

7-chloro-1-(3-hydroxycyclohexyl)-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(4-hydroxycyclohexyl)-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(cyclohex-1-en-1-yl)-4-(dimethylamino)quinazolin- 2(1H)-one

7-chloro-1-(cyclopent-1-en-1-yl)-4-(dimethylamino)quinazolin- 2(1H)-one

7-chloro-1-cyclohexyl-4-(dimethylamino)quinazolin-2(1H)-one

7-chloro-1-cyclopentyl-4-(dimethylamino)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(3-phenylpropyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-phenethoxyphenyl)quinazolin- 2(1H)-one

1-(3-((benzyloxy)methyl)phenyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one

N-benzyl-3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)- yl)benzamide

N-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-2-phenylacetamide

4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-7-(trifluoromethyl)quinazolin-2(1H)-one

7-chloro-1-(3-(2-(3-(hydroxymethyl)phenoxy)-ethyl)phenyl)-4-(methylamino)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-(pyridin-2-yloxy)ethyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-(pyridin-3-yloxy)ethyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-(pyrimidin-4-yloxy)ethyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-(thiazol-2-yloxy)ethyl)phenyl)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-(3-(2-(thiazol-2-ylamino)ethyl)phenyl)quinazolin-2(1H)-one

7-chloro-1-(3-(2-((1-methyl-1H-pyrazol-5-yl)amino)ethyl)phenyl)-4-(methylamino)-quinazolin-2(1H)-one

7-chloro-1-(3-(2-((1-methyl-1H-pyrazol-5-yl)oxy)ethyl)phenyl)-4-(methylamino)-quinazolin-2(1H)-one

4-(dimethylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin- 2(1H)-one

1-(2-chlorophenyl)-4-(dimethylamino)-7-(trifluoromethyl)-quinazolin-2(1H)-one

4-(azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)- one

4-(azetidin-1-yl)-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazolin-2(1H)-one

4-(pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin- 2(1H)-one

1-(2-chlorophenyl)-4-(pyrrolidin-1-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one

4-(3-hydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one

1-(2-chlorophenyl)-4-(3-hydroxypyrrolidin-1-yl)-7-(trifluoromethyl)-quinazolin-2(1H)-one

4-(azetidin-1-yl)-7-cyclopropyl-1-(o-tolyl)quinazolin-2(1H)-one

4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-7-(trifluoromethyl)-quinazolin-2(1H)-one

7-isopropyl-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-quinazolin-2(1H)-one

7-cyclopropyl-4-(methylamino)-1-(3-(2-phenoxyethyl)phenyl)-quinazolin-2(1H)-one

7-cyclopropyl-4-(pyrrolidin-1-yl)-1-(o-tolyl)quinazolin-2(1H)-one

2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetonitrile

methyl 2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)acetate

2-(3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-N-methylacetamide

4-cyclopropoxy-7-cyclopropyl-1-phenylquinazolin-2(1H)-one

7-cyclopropyl-4-isopropoxy-1-phenylquinazolin-2(1H)-one

7-cyclopropyl-1-phenyl-4-(2,2,2-trifluoroethoxy)quinazolin-2(1H)- one

7-cyclopropyl-4-(oxetan-3-ylmethoxy)-1-phenylquinazolin-2(1H)- one

7-cyclopropyl-4-(cyclopropylmethoxy)-1-phenylquinazolin-2(1H)- one

7-cyclopropyl-4-methoxy-1-(2-methylpyridin-3-yl)quinazolin- 2(1H)-one

1-(2-chlorophenyl)-4-isopropoxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

1-(2-chlorophenyl)-4-(2,2,2-trifluoroethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

1-(2-chlorophenyl)-4-(oxetan-3-ylmethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

1-(2-chlorophenyl)-4-(cyclopropylmethoxy)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

1-(2-chlorophenyl)-7-cyclopropyl-4-(3-hydroxy-3-methylpyrrolidin-1-yl)quinazolin-2(1H)-one

1-(2-chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-methylpyrido[2,3-d]pyrimidin-2(1H)-one

7-chloro-5-(difluoromethoxy)-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one

(R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one

7-chloro-5-methoxy-4-(methylamino)-1-(pyridin-3-yl)quinazolin- 2(1H)-one

7-chloro-5-methoxy-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

7-cyclopropyl-5-methoxy-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

7-chloro-5-ethyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one

7-chloro-5-methyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)- one

7-chloro-4-(methylamino)-1-(o-tolyl)-5-(trifluoromethoxy)quinazolin-2(1H)-one

4-amino-7-cyclopropyl-1-(o-tolyl)quinazolin-2(1H)-one

1-(2-chlorophenyl)-4-((1R,2R)-2-methoxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

1-(2-chlorophenyl)-4-((1S,2S)-2-methoxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one

7-chloro-1-((2-methoxy-1H-imidazol-4-yl)methyl)-4-(methylamino)quinazolin-2(1H)-one

7-chloro-4-(methylamino)-1-((2-(trifluoromethyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one

1-((1H-pyrazol-3-yl)methyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one

1-((1H-pyrazol-4-yl)methyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one

1-(azetidin-3-ylmethyl)-7-chloro-4-(methylamino)quinazolin- 2(1H)-one

1-(1H-benzo[d]imidazol-6-yl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one

1-(1H-benzo[d]imidazol-4-yl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one

7-chloro-1-(1H-indazol-4-yl)-4-(methylamino)quinazolin-2(1H)- one

1-(benzo[d]oxazol-6-yl)-7-chloro-4-(methylamino)quinazolin- 2(1H)-one

1-(benzo[d]thiazol-6-yl)-7-chloro-4-(methylamino)quinazolin- 2(1H)-one

7-chloro-1-(1-methyl-1H-benzo[d]imidazol-5-yl)-4-(methylamino)quinazolin-2(1H)-one

7-chloro-1-(1-methyl-1H-benzo[d]imidazol-6-yl)-4-(methylamino)quinazolin-2(1H)-one

7-chloro-1-(imidazo[1,2-a]pyridin-8-yl)-4-(methylamino)quinazolin-2(1H)-one

(R)-7-chloro-5-(2-hydroxypropoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one

(S)-7-chloro-5-(2-hydroxypropoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one

7-chloro-5-(2-methoxyethoxy)-4-(methylamino)-1-phenylquinazolin-2(1H)-one

7-chloro-4-(methylamino)-5-(oxetan-3-ylmethoxy)-1-phenylquinazolin-2(1H)-one

5-methoxy-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethyppyrido[2,3-d]pyrimidin-2(1H)-one

7-cyclopropyl-4-((2,2-difluoroethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one

1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)quinazolin-2(1H)-one

7-cyclopropyl-1-phenyl-4-((2,2,2-trifluoroethyl)amino)pyrido[2,3-d]pyrimidin-2(1H)-one

7-cyclopropyl-4-((2,2-difluoroethyl)amino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one

4-amino-7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one

7-cyclopropyl-4-methoxy-1-phenylpyrido[2,3-d]pyrimidin-2(1H)- one

7-cyclopropyl-4-(methylamino)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one

7-ethyl-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin- 2(1H)-one

7-ethyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one

1-(2-chlorophenyl)-7-ethyl-4-(methylamino)quinazolin-2(1H)-one

EMBODIMENTS

In further embodiments 1 to 34 below, the present disclosure includes:

1A. In embodiment 1A, provided is a compound of Formula (IA′), (IA),(IIA′) or (IIA) or a pharmaceutically acceptable salt thereof, where w,x, y, z, R¹ and R² are as described in the Summary above. In a firstsubembodiment of first embodiment, the compound or a pharmaceuticallyacceptable salt thereof has structure (IA). In a second subembodiment offirst embodiment, the compound or a pharmaceutically acceptable saltthereof has structure (IIA). In a third subembodiment of firstembodiment, the compound or a pharmaceutically acceptable salt thereofhas structure (IA′). In a fourth subembodiment of first embodiment, thecompound or a pharmaceutically acceptable salt thereof has structure(IIA′).

1. In embodiment 1, provided is a compound of Formula (I), (IA), (IA′),(II), (IIA), (IIA′) or a subembodiment describe herein; or apharmaceutically acceptable salt thereof, where w, x, y, z, R¹ and R²are as described in the Summary above. In a first subembodiment of firstembodiment, the compound or a pharmaceutically acceptable salt thereofhas structure (I). In a second subembodiment of first embodiment, thecompound or a pharmaceutically acceptable salt thereof has structure(II).

2. In embodiment 2, the compound of any one of embodiments 1A or 1 andsubembodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein

R¹ is R⁷ wherein R⁷ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl,fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, andheterocyclyl are unsubstituted or substituted with R^(d), R^(e), and/orR^(f); and

-   -   R² is alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸,        —NR⁹R¹⁰, or —X^(b)—R¹¹. In a first subembodiment of embodiment        2, R² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸,        —NR⁹R¹⁰, or R¹.

3. In embodiment 3, the compound of any one of embodiments TA or 1 andsubembodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein

-   -   R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, aminocarbonylalkyl, or aminosulfonylalkyl; and    -   R² is alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸,        —NR⁹R¹⁰, or —X^(b)—R¹¹. In a first subembodiment of embodiment        3, R² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸,        —NR⁹R¹⁰, or R¹¹.

4. In embodiment 4, the compound of any one of embodiments 1A or 1 andsubembodiments contained therein, or a pharmaceutically acceptable saltthereof is wherein R¹ is R⁷ wherein R⁷ is cycloalkyl, bridgedcycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl,heterocyclyl, bridged heterocyclyl, fused heterocyclyl, orspiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl isunsubstituted or substituted with R^(d), R^(e), and/or R^(f).

5. In embodiment 5, the compound of any one of embodiments 1A and 1 to 4and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof has a structure of formula (IIIa), (IIIb), (IIIc), (IIId),(IIIe), (IIIf), or (IIIg) below:

In a first sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIa). In second sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIb). In third sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIc). In fourth sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIId). In fifth sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIe). In sixth sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIf). In seventh sub-embodiment of embodiment 5, the compound or apharmaceutically acceptable salt thereof has a structure of formula(IIIg).

6. In embodiment 6, the compound of any one of embodiments TA and 1 to 5and subembodiments contained therein (e.g., compounds of formulae(IIIa), (IIIb), (IIIc), (IIId), (IIIe), (IIIf) and (IIIg)), or apharmaceutically acceptable salt thereof is wherein R² is —NR⁹R¹⁰.

7. In embodiment 7, the compound of any one of embodiments TA and 1 to 5and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is —OR⁸.

8. In embodiment 8, the compound of any one of embodiments TA and 1 to 5and subembodiments contained therein or a pharmaceutically acceptablesalt thereof is wherein R² is R.

9. In embodiment 9, the compound of any one of embodiments TA and 1 to 5and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is -(alkylene)-R¹¹. In a first subembodimentof embodiment 9, alkylene is methylene or ethylene. In a secondembodiment of embodiment 9 alkylene is methylene.

10. In embodiment 10, the compound of any one of embodiments TA and 1 to6 and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R⁹ is hydrogen, methyl, ethyl, cyclopropyl, ortrideuteromethyl. In a first subembodiment of embodiment 10, R⁹ ishydrogen, methyl, ethyl, or cyclopropyl. In a second subembodiment ofembodiment 10, R⁹ is hydrogen, methyl, or cyclopropyl. In a thirdsubembodiment of embodiment 4, R⁹ is hydrogen. In a fourth subembodimentof embodiment 10, R⁹ is methyl. In a fifth subembodiment of embodiment10, R⁹ is cyclopropyl. In a sixth subembodiment of embodiment 10, R⁹ ishydrogen or methyl. In a seventh subembodiment of embodiment 10, R⁹ istri-deuteromethyl.

11. In embodiment 11, the compound of any one of embodiments TA and 1 to6 and 10 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹⁰ is hydrogen, alkyl, deuteroalkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl, preferably R¹⁰ ishydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,alkylaminocarbonylalkyl, or dialkylaminocarbonylalkyl. In a firstsubembodiment of embodiment 11, R¹⁰ is hydrogen. In a secondsubembodiment of embodiment 11, R¹⁰ is alkyl, preferably methyl, ethyl,isopropyl, isobutyl, or tert-butyl, preferably methyl. In a thirdsubembodiment of embodiment 11, R¹⁰ is haloalkyl, preferably2,2-difluoroethyl or 2,2,2-trifluoroethyl. In a fourth subembodiment ofembodiment 11, R¹⁰ is hydroxyalkyl, preferably 2-hydroxyethyl,3-hydroxypropyl, or dihydroxypropyl. In a fifth subembodiment ofembodiment 5, R¹⁰ is aminoalkyl, preferably aminoethyl,methylaminoethyl, dimethylaminoethyl, or diethylaminoethyl. In a sixthsubembodiment of embodiment 11, R¹⁰ is alkoxyalkyl, preferablymethoxyethyl, ethoxyethyl, methoxypropyl, or ethoxypropyl. In a seventhsubembodiment of embodiment 11, R¹⁰ is alkylcarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl, preferably acetyl,methylaminocarbonyl, ethylaminocarbonyl, dimethylaminocarbonyl, ordiethylaminocarbonyl. In an eight subembodiment of embodiment 11, R¹⁰ isalkylaminocarbonylalkyl or dialkylaminocarbonylalkyl, preferablymethyaminocarbonylmethyl or dimethylaminocarbonylmethyl. In a ninthsubembodiment of embodiment 11, R¹⁰ is trideuteromethyl.

12. In embodiment 12, the compound of any one of embodiments 1A, 1 to 5and 7 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R⁸ is alkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, or aminoalkyl. In a first subembodiment of embodiment 12,R⁸ is alkyl, preferably methyl, ethyl, isopropyl, isobutyl, ortert-butyl. In a second subembodiment of embodiment 12, R⁸ is haloalkyl,preferably trifluoromethyl or 2,2,2-trifluoroethyl. In a thirdsubembodiment of embodiment 12, R⁸ is hydroxyalkyl, preferably2-hydroxyethyl, hydroxypropyl, or dihydroxypropyl. In a fourthsubembodiment of embodiment 12, R⁸ is aminoalkyl, preferably aminoethyl,methylaminoethyl, dimethylaminoethyl, or diethylaminoethyl. In a fifthsubembodiment of embodiment 12, R⁸ is alkoxyalkyl, preferablymethoxyethyl, ethoxyethyl, methoxypropyl, or ethoxypropyl.

13. In embodiment 13, the compound of any one of embodiments 1A, 1 to 7,and 10, and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R⁸ and R¹⁰ are independentlycycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl, orspirocycloalkylalkyl. In a first subembodiment of embodiment 13, R⁸ andR¹⁰ are independently cycloalkyl, preferably cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, preferably cyclopropyl, each ring mayindependently be unsubstituted or substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, hydroxy,or cyano. In a second subembodiment of embodiment 13, R⁸ and R¹⁰ areindependently cycloalkyl, preferably cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl, preferably cyclopropyl, each ring mayindependently be unsubstituted or substituted with one or twosubstituents independently selected from methyl, fluoro, or cyano. In athird subembodiment of embodiment 13, R⁸ and R¹⁰ are independentlycycloalkylalkyl, preferably cyclopropylmethyl, cyclopropylethyl,cyclobutylmethyl, cyclobutylmethyl, cyclobutylethyl, cyclopentylmethyl,cyclopentylethyl, cyclohexylmethyl, or cyclohexylethyl, the ring in eachgroup may independently be unsubstituted or substituted with one or twosubstituents independently selected from alkyl, halo, alkoxy, hydroxy,or cyano. In a fourth subembodiment of embodiment 13, R⁸ and R¹⁰ areindependently cycloalkyloxyalkyl, preferably cyclopropyloxyethyl,cyclobutyloxyethyl, cyclopentyloxyethyl, or cyclohexyloxyethyl,preferably cyclopropyloxyethyl, the ring in each group may independentlybe unsubstituted or substituted with one or two substituentsindependently selected from alkyl, halo, alkoxy, hydroxy, or cyano. In afifth subembodiment of embodiment 13, R⁸ and R¹⁰ are independentlybridged cycloalkyl or bridged cycloalkylalkyl. In a sixth subembodimentof embodiment 13, R⁸ and R¹⁰ are independently spirocycloalkyl, orspirocycloalkylalkyl. In a seventh subembodiment of embodiment 13, R⁸and R¹⁰ are independently cycloalkyl or cycloalkylalkyl, preferablycyclopropyl or cyclopropylmethyl, each ring may independently beunsubstituted or substituted with one or two substituents independentlyselected from alkyl, halo, or cyano. In an eighth subembodiment ofembodiment 13, R⁸ and R¹⁰ are independently cyclopropyl orcyclopropylmethyl, each ring may independently be unsubstituted orsubstituted with one or two substituents independently selected frommethyl, fluoro, or cyano. In a ninth subembodiment of embodiment 13, R⁸and R¹⁰ are independently R⁸ and R¹⁰ are independently cyclopropyl,cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl,(cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl,cyclopropylmethyl, 1-hydroxycyclopropmethyl, 1-fluorocyclopropmethyl,(trans)-3-hydroxy-1-methylcyclobutyl, (cis)-3-cyanocyclobutyl,1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl,(trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl,(2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl,(1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl,(1R,2R)-2-fluorocyclopropyl, 1-fluorocyclopropylmethyl,(1S,2R)-2-fluorocyclopropyl, (1R,2S)-2-fluorocyclopropyl,(1S,2S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl,(R)-1-cyclopropylethyl, or 2,2-difluorocyclopropylmethyl. In a tenthsubembodiment of embodiment 13, R⁸ and R¹⁰ are independentlycyclopropyl, cyclobutyl, 1-methylcyclopropyl,(cis)-3-hydroxy-3-methylcyclobutyl,(cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl,(trans)-3-hydroxy-1-methylcyclobutyl (cis)-3-cyanocyclobutyl,1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl,(trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl,(2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl,(1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl,(1R,2R)-2-fluorocyclopropyl, (1S,2R)-2-fluorocyclopropyl,(1R,2S)-2-fluorocyclopropyl, (1S,2S)-2-fluorocyclopropyl, or2,2-difluorocyclopropyl. In a eleventh subembodiment of embodiment 13,R⁸ and R¹⁰ are independently cyclopropylmethyl,1-hydroxycyclopropmethyl, 1-fluorocyclopropmethyl,1-fluorocyclopropylmethyl, (R)-1-cyclopropylethyl, or2,2-difluorocyclopropylmethyl.

14. In embodiment 14, the compound of any one of embodiments 1A, 1 to 7and 10, and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R⁸ and R¹⁰ are independently phenylor phenylalkyl (preferably benzyl or phenethyl) wherein phenyl, byitself or as part of aralkyl, is unsubstituted or substituted withR^(j), R^(k), and/or R^(l).

15. In embodiment 15, the compound of any one of embodiments 1 to 7 and10 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R⁸ and R¹⁰ are independentlyheteroaryl or heteroaralkyl wherein heteroaryl, by itself or as partheteroaralkyl, is unsubstituted or substituted with R^(j), R^(k), and/orR^(l). In a first subembodiment of embodiment 15, R⁸ and R¹⁰ areheteroaryl independently selected from pyrazolyl, oxazolyl, isoxazolyl,imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl,pyridazinyl, quinolinyl, isoquinolinyl, indolyl, and indazolyl,preferably pyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl,pyrimidinly, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl,and indazolyl, each ring unsubstituted or substituted with R^(j), R^(k),and/or R^(l). In a second subembodiment of embodiment 15, R⁸ and R¹⁰ areheteroaralkyl independently selected from pyrazolylmethyl,pyrazolylethyl, oxazolylmethyl, isoxazolylmethyl, imidazolylmethyl,imidazolylethyl, thienylmethyl, thienylethyl, pyrrolylmethyl,pyrrolylethyl, pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl,pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl,pyridazinylethyl, quinolinylmethyl, quinolinylethyl,isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl, indolylethyl,indazolylmethyl and indazolylethyl, preferably pyrazolylmethyl,pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl,thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl,pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl,pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl,quinolinylethyl, isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl,indolylethyl, indazolylmethyl and indazolylethyl, preferablypyrazolylmethyl or pyridinylmethyl, each ring unsubstituted orsubstituted with R^(j), R^(k), and/or R^(l). In a third subembodiment ofembodiment 15, R⁸ and R¹⁰ 1-methyl-1H-pyrazol-5-yl, isoxazol-4-yl,3-methyl-1,2,4-oxadiazol-5-yl, 5-methylisoxazol-3-yl,5-methylisoxazol-4-yl, 3-methoxyisoxazol-5-yl,3,5-dimethylisoxazol-4-yl, 3-methylisoxazol-4-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-(difluoromethyl)pyridin-4-yl, 2-(difluoromethoxy)pyridin-4-yl,5-methoxypyridin-3-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl,3-cyanopyridin-4-yl, 3-methoxypyridin-4-yl, 3-fluoropyridin-4-yl,3-chloropyridin-4-yl, 2-(trifluoromethyl)pyridin-4-yl,2-methylpyridin-4-yl, pyrimidin-5-yl, 1-methyl-1H-imidazol-4-yl,1-methylpyrazol-3-ylmethyl, 3-methoxyisoxazol-5-ylmethyl,oxazol-2-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl,isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl,1-methyl-1H-pyrazol-3-ylmethyl, 1-methyl-1H-pyrazol-4-ylmethyl,1-methyl-1H-pyrazol-5-ylmethyl, pyridin-4-ylmethyl, pyridin-3-ylmethyl,or pyridin-2-ylmethyl.

16. In embodiment 16, the compound of any one of embodiments 1A, 1 to 7and 10 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R⁸ and R¹⁰ are independentlyheterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fusedheterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridgedheterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl whereinheterocyclyl, by itself or as part of another group, is unsubstituted orsubstituted with R^(j), R^(k), and/or R^(l). In a first subembodiment ofembodiment 16, R⁸ and R¹⁰ are independently heterocyclyl, preferablyoxetanyl, azetidinyl, tetrahydrofuranyl, pyrrolidinyl, piperidinyl,piperazinyl, or morpholinyl, each ring is unsubstituted or substitutedwith R^(j), R^(k), and/or R^(l). In a second subembodiment of embodiment16, R⁸ and R¹⁰ are independently heterocyclylalkyl, preferablyoxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl,pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl,piperidinylethyl, morpholinylmethyl, or morpholinylethyl, each ring isunsubstituted or substituted with R^(j), R^(k), and/or R^(l). In a thirdsubembodiment of embodiment 16, R⁸ and R¹⁰ are independentlyheterocyclyloxyalkyl which is unsubstituted or substituted with R^(j),R^(k), and/or R^(l). In a fourth subembodiment of embodiment 16, R⁸ andR¹⁰ are independently bridged heterocyclyl, bridged heterocyclylalkyl.In a fifth subembodiment of embodiment 16, R⁸ and R¹⁰ are independentlyspiroheterocyclyl, or spiroheterocyclylalkyl.

17. In embodiment 17, the compound of any one of embodiments 1A, 1 to 5,8, and 9 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹¹ is heterocyclyl which isunsubstituted or substituted with R^(m), R^(n), and/or R^(o). In a firstsubembodiment of embodiment 17, R¹¹ is oxetanyl, azetidinyl,2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl,piperazinyl, or morpholinyl, preferably azetidin-1-yl,2-oxoazetidin-1-yl, pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl,piperidin-1-yl, piperazin-1-yl, or morpholin-4-yl, each ring isunsubstituted or substituted with R^(m), R^(n), and/or R^(o). In asecond subembodiment of embodiment 17, R¹¹ is azetidin-1-yl,4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl,4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethylazetidin-1-yl,2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl,2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl,3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl,2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl,4-methylpiperazin-1-yl, or morpholin-4-yl. In a third subembodiment ofembodiment 17, R¹¹ is 3-hydroxypyrrolidin-1-yl.

18. In embodiment 18, the compound of any one of embodiments 1A, 1 to 5,8, and 9, and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹¹ is cycloalkyl. In a firstsubembodiment of embodiment 18, R¹¹ is cycloalkyl, preferablycyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, preferablycyclopropyl, each ring may independently be unsubstituted or substitutedwith one or two substituents independently selected from alkyl, halo,alkoxy, hydroxy, or cyano.

19. In embodiment 19, the compound of any one of embodiments 1A, 1 to 5,8 and 9 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹¹ is heteroaryl which isunsubstituted or substituted with R^(j), R^(k), and/or R^(l). In a firstsubembodiment of embodiment 19, R¹¹ is pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, indolyl, and indazolyl, each ring unsubstituted orsubstituted with R^(j), R^(k), and/or R^(l). In a second subembodimentof embodiment 19, R¹¹ is pyrazolyl, imidazolyl-2-yl, imidazolyl-4-yl,thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, or isothiazol-4-yl.

20. In embodiment 20, the compound of any one of embodiments 1A, 1 to 5and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R² is hydroxyalkyl, aminoalkyl,aminocarbonylalkyl.

21. In embodiment 21, the compound of any one of embodiments 1A, 1 to 20and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R⁴ and R⁶ are independently selected fromhydrogen, methyl, chloro, fluoro, bromo, methoxy, methylsulfonyl,trifluoromethyl, trifluoromethoxy, cyano, amino, methylamino,dimethylamino, methylaminocarbonyl, or dimethylaminocarbonyl. In a firstsubembodiment of embodiment 21, R⁴ is hydrogen, fluoro, methoxy, cyanoand R⁶ is hydrogen. In a second subembodiment of embodiment 21, R⁴ andR⁶ are hydrogen. In a second subembodiment of embodiment 21, R⁴ and R⁶are hydrogen. In a third subembodiment of embodiment 21, R⁴ and R⁶ areindependently selected from hydrogen, methyl, chloro, fluoro, methoxy,methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino,methylamino, dimethylamino, methylaminocarbonyl, ordimethylaminocarbonyl. In a fifth subembodiment of embodiment 21, R⁴ ishydrogen, fluoro, bromo, methyl, methoxy, or cyano and R⁶ is hydrogen.

22. In embodiment 22, the compound of any one of embodiments 1A, 1 to 21and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R⁵ is alkyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl,alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,heterocyclyloxyalkylamino, preferably R⁵ is alkyl, alkoxy, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl, heteroaryl,heterocyclyl, wherein heterocyclyl or heteroaryl, by itself or as partof another group, is unsubstituted or substituted with R^(a), R^(b),and/or R^(c) independently selected from alkyl, cycloalkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, oraminoalkyl. In a first subembodiment of embodiment 22, R⁵ is methyl,ethyl, isopropyl, tert-butyl, methoxy, ethoxy, fluoro, chloro, bromo,trifluoromethyl, difluoromethyl, trifluoromethoxy, difluoromethoxy,cyclopropyl, cyclopentyl, cyano, methylsulfonyl, methylamino, ordimethylamino. In a second subembodiment of embodiment 22, R⁵ ishydroxymethyloxy, hydroxyethyloxy, hydroxymethylamino,hydroxyethylamino, aminoethyloxy, methylaminoethyloxy,dimethylaminoethyloxy, diethylaminoethyloxy, aminoethylamino,methylaminoethylamino, dimethylaminoethylamino, ordiethylaminoethylamino. In a third subembodiment of embodiment 22, R⁵ is5- or 6-membered heteroaryl such as pyrazolyl, imidazolyl, thienyl,thiazolyl, oxazolyl, isoxazolyl, pyridinyl, or pyrimidinyl each of whichis unsubstituted or substituted with R^(a), R^(b), and/or R^(c)independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy,alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl.In a fourth subembodiment of embodiment 22, R⁵ is 4- or 6-memberedheterocyclyl, preferably oxetan-3-yl, pyrrolidin-1-yl,tetrahydrofuranyl, 2-oxoazetidin-1-yl, 2-oxopyrrolidin-1-yl each ring isunsubstituted or substituted with R^(a) and/or R^(b). In a fifthsubembodiment of embodiment 22, R⁵ is halo, alkyl, haloalkyl, orcycloalkyl. In a sixth subembodiment of embodiment 22, R⁵ is chloro,methyl, ethyl, trifluoromethyl, or cyclopropyl. In a seventhsubembodiment of embodiment 22, R⁵ is trifluoromethyl,1,1-difluoroethyl, or cyclopropyl. In an eighth subembodiment ofembodiment 22, R⁵ is chloro, methyl, ethyl, trifluoromethyl,1,1-difluoroethyl, or cyclopropyl.

23. In embodiment 23, the compound of any one of embodiments 1A, 1 to 23and subembodiments contained therein, or a pharmaceutically acceptablesalt thereof is wherein R³ is hydrogen, alkyl, alkoxy, alkylsulfonyl,halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl,alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itselfor as part of another group, is unsubstituted or substituted with R^(a),R^(b), and/or R^(c) independently selected from alkyl, cycloalkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl,alkoxyalkyl, or aminoalkyl. In a first subembodiment of embodiment 23,R³ is hydrogen. In a second subembodiment of embodiment 23, R³ ismethyl, ethyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl,difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano,methylsulfonyl, aminocarbonyl, methylamino, or dimethylamino. In a thirdsubembodiment of embodiment 23, R³ is hydroxymethyloxy, hydroxyethyloxy,hydroxymethylamino, hydroxyethylamino, aminoethyloxy,methylaminoethyloxy, dimethylaminoethyloxy, diethylaminoethyloxy,aminoethylamino, methylaminoethylamino, dimethylaminoethylamino, ordiethylaminoethylamino. In a fourth subembodiment of embodiment 23, R³is heteroaryl, preferably 5- or 6-membered heteroaryl such as pyrazolyl,imidazolyl, triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl,pyridinyl, or pyrimidinyl each ring either unsubstituted or substitutedwith R^(a), R^(b), and/or R^(c). In a fifth subembodiment of embodiment23, R³ is heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclyloxyalkoxy, heterocyclyloxyalkylamino,wherein heterocyclyl or heteroaryl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(a), R^(b), and/or R^(c).In a sixth subembodiment of embodiment 3, R³ is oxopyrrolidinyl,morpholin-4-yl, or 2-morpholin-4-ylethyloxy. In a fifth subembodiment ofembodiment 23, R³ is hydrogen or methoxy. In an eighth subembodiment ofembodiment 23, when R³ is a group of second, third, fourth, fifth orsixth subembodiment, then R² is amino or methylamino, R⁴ and R⁶ arehydrogen and R⁵ is other than hydrogen.

24. In embodiment 24, the compound of any one of embodiments 1A, 1, 3, 5to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R^(t) is alkyl, preferably methyl,ethyl, or isopropyl.

25. In embodiment 25, the compound of any one of embodiments 1A, 1, 3, 5to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is haloalkyl, preferablytrifluoromethyl.

26. In embodiment 26, the compound of any one of embodiments 1A, 1, 3, 5to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, or aminosulfonylalkyl.

27. In embodiment 27, the compound of any one of embodiments 1A, 1, 2, 4to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is cycloalkyl,bridged cycloalkyl, fused cycloalkyl, or spirocycloalkyl. In a firstsubembodiment of embodiment 27, R⁷ is cycloalkyl, preferablycyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl which isunsubstituted or substituted with one or two substituents independentlyselected from alkyl, hydroxy, alkoxy, cyano or halo. In a firstsubembodiment of embodiment 27, R⁷ is cycloalkenyl, cyclopentenyl, orcyclohexenyl which is unsubstituted or substituted with one or twosubstituents independently selected from alkyl, hydroxy, alkoxy, cyanoor halo.

28. In embodiment 28, the compound of any one of embodiments 1A, 1, 2, 4to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is aryl which isunsubstituted or substituted with R^(d), R^(e), and/or R^(f) wherein R′is selected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo,cyano, optionally substituted aryl, optionally substituted heteroaryl,or optionally substituted heterocyclyl. In a first subembodiment ofembodiment 28, R⁷ is phenyl which is unsubstituted or substituted withR^(d), R^(e), and/or R^(f). In a second subembodiment of embodiment 28,R⁷ is phenyl which is unsubstituted or substituted with R^(d), R^(e),and/or R^(f) where R^(d) and R^(e) are independently selected frommethyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl,cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R^(f) is selected from hydroxy, fluoro, chloro,cyano or methyl. In a third subembodiment of embodiment 28, R⁷ is phenylwhich is substituted with R^(d), R^(e), and/or R^(f) where R^(d) andR^(e) are independently selected from methyl, ethyl, fluoro, chloro,bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl,methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R^(f)is selected from hydroxy, fluoro, chloro, cyano or methyl and whereinR^(d), R^(e), and/or R^(f) are attached to carbon atoms on the phenylring that are ortho or meta to the carbon atom of the phenyl ringattached to quinazolone nitrogen. In a fourth subembodiment ofembodiment 28, R⁷ is phenyl which is unsubstituted or substituted withR^(e) and/or R^(f) where R^(e) is methyl, ethyl, fluoro, chloro, bromo,methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl,aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R′ is fluoro,chloro, cyano or methyl and wherein R^(f) is attached to carbon atoms onthe phenyl ring that is ortho to the carbon atom of the phenyl ringattached to quinazolone nitrogen. In a fifth subembodiment of embodiment28, R⁷ is phenyl which is unsubstituted or substituted with R^(f)wherein R is fluoro, chloro, bromo, or methyl and wherein R^(f) isattached to carbon atoms on the phenyl ring that is ortho to the carbonatom of the phenyl ring attached to quinazolone nitrogen.

29. In embodiment 28, the compound of any one of embodiments 1A, 1, 2,and 4 to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is heteroarylwhich is unsubstituted or substituted with R^(d), R^(e), and/or R^(f)wherein R^(f) is selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, halo, cyano, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted heterocyclyl. In afirst subembodiment of embodiment 29, R⁷ is 5 or 6-membered heteroarylring such as pyrrolyl, pyrazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyridazinyl, or pyrazinyl, which is unsubstituted orsubstituted with R^(d), R^(e), and/or R^(f). In a second subembodimentof embodiment 29, R^(d) and R^(e) are independently selected frommethyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl,cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R is selected from hydroxy, fluoro, chloro, cyano ormethyl. In a third subembodiment of embodiment 29, R^(d), R^(e), and/orR^(f) where R^(d) and R^(e) independently selected from methyl, ethyl,fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano,methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R^(f) is selected from hydroxy, fluoro, chloro,cyano or methyl and wherein R^(d), R^(e), and/or R^(f) are attached tocarbon atoms on the heteroaryl ring that are ortho or meta to the carbonatom of the heteroaryl ring attached to quinazolone nitrogen. In afourth subembodiment of embodiment 29, R⁷ is pyridinyl or pyrimidinyl,preferably pyridin-3-yl or pyrimidin-4-yl, which is unsubstituted orsubstituted with R^(e) and/or R^(f) where R^(e) is methyl, ethyl,fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano,methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R^(f) is fluoro, chloro, cyano or methyl and whereinR is attached to carbon atoms on the pyridinyl or pyrimidinyl ring thatis ortho to the carbon atom of the phenyl ring attached to quinazolonenitrogen. In a fifth subembodiment of embodiment 29, R⁷ is pyridinyl,preferably pyridin-2-yl or pyridin-3-yl, which is unsubstituted orsubstituted with R^(f) where R^(f) is fluoro, chloro, or methyl andwherein R^(f) is attached to carbon atoms on the pyridinyl ring that isortho to the carbon atom of the phenyl ring attached to quinazolonenitrogen.

30. In embodiment 30, the compound of any one of embodiments 1A, 1, 2,and 4 to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is heterocyclyl,bridged heterocyclyl, fused heterocyclyl, or spiroheterocyclyl, whereinheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f) wherein R^(f) is selected from alkyl, haloalkyl, haloalkoxy,alkoxy, hydroxy, halo, cyano, optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted heterocyclyl. In afirst subembodiment of embodiment 30, R⁷ is pyrrolidinyl, piperidinyl,piperazinyl, oxetanyl, tetrahydrofuranyl, or morpholinyl, each ringindependently unsubstituted or substituted with R^(d), R^(e), and/orR^(f). In a second subembodiment of embodiment 30, R⁷ is pyrrolidinyl,piperidinyl, piperazinyl, oxetanyl, tetrahydrofuranyl, or morpholinyl,each ring independently unsubstituted or substituted with R^(d), R^(e),and/or wherein R^(d), R^(e), and/or R^(f) independently selected frommethyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, hydroxy,methylsulfonyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl.

31. In embodiment 31, the compound of any one of embodiments 1A, 1, 2,and 4 to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is aryl which issubstituted with R^(d), R^(e), and/or R^(f) wherein R^(f) is —X^(c)—R¹²where X^(c) is alkylene or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl. In a first subembodiment of embodiment 28, R⁷is phenyl substituted with R^(d), R^(e), and/or R^(f). In a secondsubembodiment of embodiment 28, R⁷ is phenyl which is unsubstituted orsubstituted with R^(d), R^(e), and/or R^(f) where R^(d) and R^(e) areindependently selected from methyl, ethyl, fluoro, chloro, bromo,methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl,aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R^(f) is selectedfrom 2-phenyloxyethyl, 2-phenylaminoethyl, 2-phenylethyloxy, or2-phenylaminoethyl wherein phenyl is optionally substituted with one ortwo substituents independently selected from methyl, fluoro, chloro,methoxy, hydroxy, trifluoromethyl, or trifluoromethoxy. In a thirdsubembodiment of embodiment 31, R^(f) is attached to a carbon atom onthe phenyl ring that are ortho or meta to the carbon atom of the phenylring attached to quinazolone nitrogen.

32. In embodiment 32, the compound of any one of embodiments 1A, 1, 2,and 4 to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is R⁷ wherein R⁷ is heteroarylwhich is substituted with R^(d), R^(e), and/or R^(f) wherein R^(f) is—X^(c)—R¹² where X^(c) is alkylene or heteroalkylene and R¹² isoptionally substituted aryl, optionally substituted heteroaryl, oroptionally substituted heterocyclyl. In a first subembodiment ofembodiment 32, R⁷ is 5 or 6-membered heteroaryl ring such as pyrrolyl,pyrazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl,or pyrazinyl, which is unsubstituted or substituted with R^(d), R^(e),and/or R^(f). In a second subembodiment of embodiment 32, R^(d) andR^(e) are independently selected from methyl, ethyl, fluoro, chloro,bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl,methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R^(f)is selected from 2-phenyloxyethyl, 2-phenylaminoethyl, 2-phenylethyloxy,or 2-phenylaminoethyl wherein phenyl is optionally substituted with oneor two substituents independently selected from methyl, fluoro, chloro,methoxy, hydroxy, trifluoromethyl, or trifluoromethoxy. In a thirdsubembodiment of embodiment 32, R^(f) is attached to an atom of theheteroaryl ring that are ortho or meta to the carbon atom of theheteroaryl ring attached to quinazolone nitrogen.

33. In embodiment 33, the compound of any one of embodiments 1A, 1, 2, 4to 23 and subembodiments contained therein, or a pharmaceuticallyacceptable salt thereof is wherein R¹ is —X^(a)—R⁷ wherein X^(a) isalkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl,fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, orheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f).

It is understood that the embodiments set forth above include allcombination of embodiments and subembodiments listed therein. Forexample, the R¹ group listed in embodiment 30 and/or first and/or secondsubembodiments therein, can independently combine with one or more ofthe embodiments 1-28 and 31 to 33 and/or subembodiments containedtherein.

The present disclosure includes additional embodiment 35 to 90 below.

35. A compound of Formula (IA):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy,heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocyclylalkyloxy, heterocyclyloxyalkoxy, orheterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itselfor as part of another group, is unsubstituted or substituted with R^(a),R^(b), and/or R^(c) independently selected from alkyl, cycloalkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl; provided that: (i) no more than two of w, x, y,and z can be N and (ii) at least one of R³, R⁴, R⁵, and R⁶ is other thanhydrogen;

R¹ is R⁷ wherein R⁷ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl,fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, orheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f);

R² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or —X^(b)—R¹¹wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl,        cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹² where X^(c) is bond,alkylene, or heteroalkylene and R¹² is optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl; or

a pharmaceutically acceptable salt thereof; provided that:

(1) when

where: (a) when R² is piperazin-1-yl, 2-methylpiperazin-1-yl, or1H-benzo[d][1,2,3]triazol-1-yl, R³ and R⁶ are hydrogen, R⁴ is chloro andR⁵ is bromo or 5-methylindazol-4-yl, then R is not 2-isopropylphenyl;(b) when R² and R⁶ are methyl and R³, R⁴, and R⁵ are hydrogen; or R² andR³ are methyl and R⁴, R⁵, and R⁶ are hydrogen, then R¹ is not 2,5-, 2,6-or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy-or 2-methyl-8-methoxyquinolin-4-yl; (c) when R² is amino or acetylamino,R⁴ is dimethylamino, and R³, R⁵, and R⁶ are hydrogen, then R is not4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) when R⁵ is fluoro,R³, R⁴ and R⁶ are hydrogen, and R² is4-aminocarbonylmethyl-2-methylphenylamino, then R¹ is not4-fluoro-2-(2-thiazol-2-ylmethoxy)phenyl,4-fluoro-2-(2-pyridin-2-ylmethoxy)phenyl, or 4-chloro-2-methoxyphenyl;(e) when R⁶ is fluoro, R³, R⁴ and R⁵ are hydrogen, and R² is4-aminocarbonylmethyl-2-methylphenylamino, then R¹ is not4-fluoro-2-methoxyphenyl; (f) when R¹ is 4-chloro-2-ethoxyphenyl, R⁵ isfluoro, and R³, R⁴ and R⁶ are hydrogen, then R² is not3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino;

(2) when

then when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, R⁵ is amino, and R³is methoxy; then R² is not amino; and

(3) when

then when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, one of R⁴ and R⁵ ishydrogen, and the other of R⁴ and R⁵ is methyl or both of R⁴ and R⁵ aremethyl, then R² is not amino.

36. The compound of embodiment 35 wherein the compound has a structureof Formula (I):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N; wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is R⁷ wherein R⁷ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl,fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, orheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f);

R² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or —X^(b)—R¹¹wherein: R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fusedheterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridgedheterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, whereinaryl, heteroaryl, or heterocyclyl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(g), R^(h), and/or R^(i);

R⁹ is hydrogen, alkyl or cycloalkyl; and

R¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl,cycloalkoxyalkyl, bridged cycloalkyl, bridged cycloalkylalkyl, fusedcycloalkyl, spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,heteroaryl, heteroaralkyl, heteroarylcarbonyl, heterocyclyl,heterocyclylalkyl, heterocyclylcarbonyl, heterocyclyloxyalkyl, fusedheterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridgedheterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, whereinaryl, heteroaryl, or heterocyclyl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(j), R^(k), and/or R^(l);

-   -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or —X^(c)—R¹² whereX^(c) is bond, alkylene or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, or optionallysubstituted heterocyclyl; or

a pharmaceutically acceptable salt thereof.

37. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having a structure of formula (IIIa), (IIIb),(IIIc), (IIId), (IIIe), or (IIIg) below:

38. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIa).

39. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIb).

40. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIc).

41. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIId).

42. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIe).

43. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIf).

44. The compound of embodiment 35 or 36, or a pharmaceuticallyacceptable salt thereof having structure of formula (IIIg).

45. The compound of any one of embodiments 35 to 44 wherein R² is—NR⁹R¹⁰.

46. The compound of any one of embodiments 35 to 44 wherein R² is —OR⁸.

47. The compound of any one of embodiments 35 to 44 wherein R² is R¹¹.

48. The compound of any one of embodiments 35 to 45 wherein R⁹ isdeuteroalkyl, preferably trideuteromethyl.

49. The compound of any one of embodiments 35 to 45 wherein R⁹ ishydrogen.

50. The compound of any one of embodiments 35 to 45 wherein R⁹ is alkyl,preferably methyl or ethyl.

51. The compound of any one of claims embodiments 35 to 45 wherein R⁹ iscycloalkyl, preferably cyclopropyl.

52. The compound of any one of embodiments 35 to 45 and 49 to 51 whereinR¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonylalkyl, ordialkylaminocarbonylalkyl.

53. The compound of embodiment 52 or a pharmaceutically acceptable saltthereof wherein R¹⁰ is hydrogen.

54. The compound of embodiment 46 or 52 or a pharmaceutically acceptablesalt thereof wherein R⁸ and R¹⁰ are alkyl, preferably methyl.

55. The compound of claim embodiment 52 or a pharmaceutically acceptablesalt thereof wherein R¹⁰ is alkylaminocarbonylalkyl, ordialkylaminocarbonylalkyl, preferably methyaminocarbonyl-methyl ordimethylaminocarbonylmethyl.

56. The compound of any one of embodiments 35 to 46 and 49 to 51 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areindependently phenyl or phenylalkyl, preferably benzyl or phenethyl,wherein phenyl, by itself or as part of benzyl and phenethyl, isunsubstituted or substituted with R^(j), R^(k), and/or R^(l).

57. The compound of any one of embodiments 35 to 46 and 49 to 51 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areindependently cycloalkyl or cycloalkylalkyl, each ring may independentlybe unsubstituted or substituted with one or two substituentsindependently selected from alkyl, halo, or cyano.

58. The compound of any one of embodiments 35 to 46 and 49 to 51 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areindependently heteroaryl or heteroaralkyl wherein heteroaryl, by itselfor as part heteroaralkyl, is unsubstituted or substituted with R^(j),R^(k), and/or R^(l).

59. The compound of embodiment 58 or a pharmaceutically acceptable saltthereof wherein R⁸ and R¹⁰ are heteroaryl independently selected frompyrazolyl, imidazolyl, thienyl, pyrrolyl, pyridinyl, pyrimidinly,pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, indolyl, andindazolyl, each ring unsubstituted or substituted with R^(j), R^(k),and/or R^(l).

60. The compound of embodiment 58 or a pharmaceutically acceptable saltthereof wherein R⁸ and R¹⁰ are heteroaralkyl independently selected frompyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl,thienylmethyl, thienylethyl, pyrrolylmethyl, pyrrolylethyl,pyridinylmethyl, pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl,pyrazinylmethyl, pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl,quinolinylmethyl, quinolinylethyl, isoquinolinylmethyl,isoquinolinylethyl, indolylmethyl, indolylethyl, indazolylmethyl andindazolylethyl, each ring unsubstituted or substituted with R^(j),R^(k), and/or R^(l).

61. The compound of any one of embodiments 35 to 46 and 49 to 51 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areindependently heterocyclyl, preferably oxetanyl, azetidinyl,tetrahydrofuranyl, pyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl, each ring is unsubstituted or substituted with R^(j),R^(k), and/or R^(l).

62. The compound of any one of embodiments 35 to 46 and 49 to 51 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areindependently independently heterocyclylalkyl, preferablyoxetanylmethyl, oxetanylethyl, azetidinylmethyl, azetidinylethyl,pyrrolidinylmethyl, pyrrolidinylethyl, piperidinylmethyl,piperidinylethyl, morpholinylmethyl, or morpholinylethyl, each ring isunsubstituted or substituted with R^(j), R^(k), and/or R^(l).

63. The compound of any one of embodiments 35 to 44 and 47 or apharmaceutically acceptable salt thereof wherein R² is R¹¹ wherein R¹¹is heterocyclyl which is unsubstituted or substituted with R^(m), R^(n),and/or R^(o).

64. The compound of embodiment 63 or a pharmaceutically acceptable saltthereof wherein R¹¹ is oxetanyl, azetidinyl, 2-oxoazetidinyl,pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl, piperazinyl, ormorpholinyl, preferably azetidin-1-yl, 2-oxoazetidin-1-yl,pyrrolidin-1-yl, 2-oxopyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl,or morpholin-4-yl, each ring is unsubstituted or substituted with R^(m),R^(n), and/or R^(o), preferably R¹¹ is azetidin-1-yl,4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl,4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethyl-azetidin-1-yl,2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl,2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl,3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl,2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl,4-methylpiperazin-1-yl, or morpholin-4-yl.

65. The compound of any one of embodiments 35 to 44 and 47, or apharmaceutically acceptable salt thereof wherein R² is R¹¹ wherein R¹¹is heteroaryl which is unsubstituted or substituted with R^(m), R^(n),and/or R^(o), preferably R¹¹ is pyrazolyl, imidazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thienyl, pyrrolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, indolyl, and indazolyl, each ring unsubstituted orsubstituted with R^(m), R^(n), and/or R^(o).

66. The compound of any one of embodiments 35 to 44, or apharmaceutically acceptable salt thereof wherein R² is hydroxyalkyl,aminoalkyl, or aminocarbonylalkyl.

67. The compound of any one of embodiments 35 to 66, or apharmaceutically acceptable salt thereof wherein R⁵ is alkyl, alkoxy,halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, aminocarbonyl,heteroaryl, heterocyclyl, wherein heterocyclyl or heteroaryl isunsubstituted or substituted with R^(a), R^(b), and/or R^(c)independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy,alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl.

68. The compound of embodiment 67, or a pharmaceutically acceptable saltthereof wherein R⁵ is methyl, ethyl, isopropyl, tert-butyl, methoxy,ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyclopentyl, cyano,pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl,pyridinyl, pyrimidinyl, oxetan-3-yl, pyrrolidin-1-yl, tetrahydrofuranyl,2-oxoazetidin-1-yl, or 2-oxopyrrolidin-1-yl, wherein heterocyclyl orheteroaryl rings are unsubstituted or substituted with R^(a), R^(b),and/or R^(c) independently selected from alkyl, cycloalkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, oraminoalkyl.

69. The compound of embodiment 67, or a pharmaceutically acceptable saltthereof wherein R⁵ is chloro, methyl, ethyl, trifluoromethyl,1,1-difluoroethyl, or cyclopropyl.

70. The compound of embodiment 68 wherein R⁵ is chloro, trifluoromethyl,or ethyl.

71. The compound of any one of embodiments 35 to 70, or apharmaceutically acceptable salt thereof wherein R⁴ and R⁶ areindependently selected from hydrogen, methyl, chloro, fluoro, methoxy,methylsulfonyl, trifluoromethyl, trifluoromethoxy, cyano, amino,methylamino, dimethylamino, methylaminocarbonyl, ordimethylaminocarbonyl.

72. The compound of any one of embodiments 35 to 70, or apharmaceutically acceptable salt thereof wherein R⁴ is hydrogen, fluoro,methoxy, cyano and R⁶ is hydrogen.

73. The compound of any one of embodiments 35 to 70, or apharmaceutically acceptable salt thereof wherein R⁴ is hydrogen or bromoand R⁶ is hydrogen.

74. The compound of any one of claims embodiments 35 to 70, or apharmaceutically acceptable salt thereof wherein R⁴ and R⁶ are hydrogen.

75. The compound of any one of embodiments 35 to 74, or apharmaceutically acceptable salt thereof wherein R³ is hydrogen, alkyl,alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano,amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl.

76. The compound of embodiment 75 or a pharmaceutically acceptable saltthereof wherein

R³ is hydrogen.

77. The compound of embodiment 75 or a pharmaceutically acceptable saltthereof wherein R³ is methyl, ethyl, methoxy, ethoxy, fluoro, chloro,bromo, trifluoromethyl, difluoromethyl, trifluoromethoxy,difluoromethoxy, cyclopropyl, cyano, methylsulfonyl, aminocarbonyl,methylamino, or dimethylamino.

78. The compound of any one of embodiments 35 to 74, or apharmaceutically acceptable salt thereof wherein R³ is heteroaryl,preferably 5- or 6-membered heteroaryl such as pyrazolyl, imidazolyl,triazolyl, thienyl, thiazolyl, oxazolyl, isoxazolyl, pyridinyl, orpyrimidinyl, each ring either unsubstituted or substituted with R^(a),R^(b), and/or R^(c).

79. The compound of any one of embodiments 35 to 74, or apharmaceutically acceptable salt thereof wherein R³ is heterocyclyl,preferably, oxopyrrolidinyl, morpholin-4-yl, or2-morpholin-4-ylethyloxy.

80. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ iscycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl, orcyclohexyl, each ring is either unsubstituted or substituted with one ortwo substituents independently selected from alkyl, hydroxy, alkoxy,cyano or halo.

81. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ isphenyl which is unsubstituted or substituted with R^(d), R^(e), and/orR^(f) where R^(d) and R^(e) are independently selected from methyl,ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl, cyano,methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R^(f) is selected from hydroxy, fluoro, chloro,cyano. and methyl.

82. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ isphenyl which is unsubstituted or substituted with R^(f) wherein R^(f) isfluoro, chloro, bromo, or methyl and wherein R^(f) is attached to carbonatoms on the phenyl ring that is ortho to the carbon atom of the phenylring attached to quinazolone nitrogen.

83. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ is5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which isunsubstituted or substituted with R^(d) and/or R^(e) independentlyselected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy,cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl,2-hydroxyethyl, or 3-hydroxypropyl and/or R^(f) selected from hydroxy,fluoro, chloro, cyano, and methyl.

84. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ isphenyl which is substituted with R^(d), R^(e), and/or R^(f) where R^(d)and R^(e) are independently selected from methyl, ethyl, fluoro, chloro,bromo, methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl,methoxymethyl, aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R^(f)is selected —X^(c)R¹² where X^(c) is alkylene or heteroalkylene,preferably heteroalkylene.

85. The compound of any one of embodiments 35 to 79, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ is5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which issubstituted with R^(d), R^(e), and/or R^(f) where R^(d) and R^(e) areindependently selected from methyl, ethyl, fluoro, chloro, bromo,methoxy, ethoxy, cyclopropyl, cyano, methylsulfonyl, methoxymethyl,aminomethyl, 2-hydroxyethyl, or 3-hydroxypropyl and R^(f) is selected—X^(c)R¹² where X^(c) is alkylene or heteroalkylene, preferablyheteroalkylene.

86 A pharmaceutical composition comprising a compound of any one ofembodiments 35 to 85, or a pharmaceutically acceptable salt thereof atleast one pharmaceutically acceptable excipient.

87. A method for treating a disease mediated by MAT2A in a patientcomprising administering to the patient a therapeutically effectiveamount of:

(a) a compound of Formula (IIA):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N, wherein:

R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy,heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocyclylalkyloxy, heterocyclyloxyalkoxy, orheterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itselfor as part of another group, is unsubstituted or substituted with R^(a),R^(b), and/or R^(c) independently selected from alkyl, cycloalkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

R⁵ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo,haloalkyl, haloalkoxy, cycloalkyl, cyano, amino, alkylamino,dialkylamino, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl;

R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano, amino,alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl; provided that: (i) no more than two of w, x, y,and z can be N and (ii) at least one of R³, R⁴, R⁵, and R⁶ is other thanhydrogen;

R¹ is R⁷ wherein R⁷ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridged heterocyclyl,fused heterocyclyl, or spiroheterocyclyl, wherein aryl, heteroaryl, orheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f);

R² is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or —X^(b)—R¹¹wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,        alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl,        cyanoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, substituted cycloalkyl, substituted        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and

R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and

R^(f), R^(i), R^(l), and R^(o) are independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, amino,cycloalkylsulfonylamino, cyano, cyanoalkyl, alkoxycarbonylalkyl,carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹² where X^(c) is bond,alkylene, or heteroalkylene and R¹² is optionally substituted aryl,optionally substituted heteroaryl, and optionally substitutedheterocyclyl;

(b) a compound of Formula (II):

where:

w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N; wherein:

-   -   R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,        hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,        alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino,        heteroaryl, heteroaryloxy, heteroarylamino, heterocyclyl,        heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy, or        heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl,        by itself or as part of another group, is unsubstituted or        substituted with R^(a), R^(b), and/or R^(c) independently        selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy,        hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;    -   R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,        alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,        cyano, amino, alkylamino, dialkylamino, aminocarbonyl,        alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i)        no more than two of w, x, y, and z can be N and (ii) at least        one of R³, R⁴, R⁵, and R⁶ is other than hydrogen;

R¹ is alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, or —X^(a)—R⁷ wherein X^(a) is abond or alkylene and R⁷ is cycloalkyl, bridged cycloalkyl, fusedcycloalkyl, spirocycloalkyl, aryl, heteroaryl, heterocyclyl, bridgedheterocyclyl, fused heterocyclyl, or spiroheterocyclyl, wherein aryl,heteroaryl, or heterocyclyl is unsubstituted or substituted with R^(d),R^(e), and/or R^(f);

R² is hydrogen, alkyl, halo, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or—X^(b)—R¹¹ wherein:

-   -   R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,        cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged        cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,        spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl,        heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl,        heterocyclyloxyalkyl, fused heterocyclyl, fused        heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(g),        R^(h), and/or R^(i);    -   R⁹ is hydrogen, alkyl or cycloalkyl; and    -   R¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,        aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,        dialkylaminocarbonyl, aminocarbonylalkyl, cycloalkyl,        cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl, bridged        cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,        spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,        heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,        heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl,        fused heterocyclylalkyl, bridged heterocyclyl, bridged        heterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl,        wherein aryl, heteroaryl, or heterocyclyl, by itself or as part        of another group, is unsubstituted or substituted with R^(j),        R^(k), and/or R^(l);    -   X^(b) is a bond or alkylene; and    -   R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,        spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl,        fused heterocyclyl, or spiroheterocyclyl, wherein heteroaryl or        heterocyclyl is unsubstituted or substituted with R^(m), R^(n),        and/or R^(o); and    -   R^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) are        independently selected from alkyl, haloalkyl, haloalkoxy,        alkoxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,        hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,        alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino,        aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,        heterocyclylcarbonyl, and ureido; and    -   R^(f), R^(i), R^(l), and R^(o) are independently selected from        alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, or        —X^(c)—R¹² where X^(c) is bond, alkylene or heteroalkylene and        R¹² is optionally substituted aryl, optionally substituted        heteroaryl, or optionally substituted heterocyclyl; or

a pharmaceutically acceptable salt thereof; or

(c). a compound of any one of embodiments 35 to 85, or apharmaceutically acceptable salt thereof.

88. The method of embodiment 87, wherein the disease is cancer.

89. A method of treating a MTAP null cancer in a patient comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (IIA) or (II) as defined in claim 87, apharmaceutically acceptable salt thereof; or

a compound of any one of embodiments 35 to 85 or a pharmaceuticallyacceptable salt thereof optionally in a pharmaceutical composition.

90. A method for treating a cancer in a patient, wherein the cancer ischaracterized by a reduction or absence of MTAP gene expression, theabsence of the MTAP gene, or reduced function of MTAP protein,comprising administering to the subject a therapeutically effectiveamount of of a compound of Formula (IIA) or (II) as defined inembodiment 87, a pharmaceutically acceptable salt thereof; or

a compound of any one of embodiments 35 to 85 or a pharmaceuticallyacceptable salt thereof optionally in a pharmaceutical composition.General Synthetic

General Synthesis

Compounds of this disclosure can be made by the methods depicted in thereaction schemes shown below.

The starting materials and reagents used in preparing these compoundsare either available from commercial suppliers such as Aldrich ChemicalCo., (Milwaukee, Wis.), Bachem (Torrance, Calif.), or Sigma (St. Louis,Mo.) or are prepared by methods known to those skilled in the artfollowing procedures set forth in references such as Fieser and Fieser'sReagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons,1991); Rodd's Chemistry of Carbon Compounds, Volumes 1-5 andSupplementals (Elsevier Science Publishers, 1989); Organic Reactions,Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced OrganicChemistry, (John Wiley and Sons, 4th Edition) and Larock's ComprehensiveOrganic Transformations (VCH Publishers Inc., 1989). These schemes aremerely illustrative of some methods by which the compounds of thisdisclosure can be synthesized, and various modifications to theseschemes can be made and will be suggested to one skilled in the artreading this disclosure. The starting materials and the intermediates,and the final products of the reaction may be isolated and purified ifdesired using conventional techniques, including but not limited tofiltration, distillation, crystallization, chromatography and the like.Such materials may be characterized using conventional means, includingphysical constants and spectral data.

Unless specified to the contrary, the reactions described herein takeplace at atmospheric pressure over a temperature range from about −78°C. to about 150° C., such as from about 0° C. to about 125° C. andfurther such as at about room (or ambient) temperature, e.g., about 20°C.

Compounds of Formula (I) and (II) and the subembodiments describedherein where w, x, y, and z are not nitrogen, R² is other than hydrogen,and other groups are as defined in the Summary can be prepared themethod illustrated and described in Scheme 1 below.

2,4-Dioxoquinazoline compound for formula 1, where R¹, R³, R⁴, R⁵ and R⁶are as described in Summary or a precursor group thereof, can be readilyconverted to a compound of Formula (I) where R² is halo by methods wellknown in the art. For example, treatment of compound 1 with POCl₃ in thepresence of an organic base such as triethylamine in an inert organicsolvent provides a compound of Formula (I) where R² is chloro, which canthen be converted to compounds of Formula (I) where R² is other thanhalo by methods well known in the art. For example, compounds of Formula(I) where R² is —NR⁹R¹⁰, heterocycle containing at least a nitrogenatom, or heteroaryl with a basic nitrogen can be prepared by treatingcorresponding compound of Formula (I) where R² is chloro with an amineof formula —NR⁹R¹⁰, heterocycle containing at least a nitrogen atom, andheteroaryl with a basic nitrogen, in the presence of a based in thepresence of a base such as triethylamine, pyridine, diisopropylamine inan organic solvent such as DMF, and the like. Amine of formula —NR⁹R¹⁰or heterocycle containing at least a nitrogen atom are commerciallyavailable. For example, methylamine, dimethylamine, ethylamine,dimethylamine, cyclopropylamine, 2-aminooxetane,tetrahydrofuran-2-amine, benzylamine, azetidine, pyrrolidine,piperidine, piperazine, morpholine, pyrazole, 2-pyridineamine,3-pyridineamine, 3-pyridineamine, and cyclopropylmethylamine arecommercially available.

Alternatively, compounds containing —NR⁹R¹⁰ can be from compounds ofFormula (I) where R² is —NH₂ under alkylation or arylation conditions bymethods well known in the art.

Compound of Formula (I) where R² is R¹¹ where R¹¹ is heteroaryl can beprepared from compounds of Formula (I) where R² is halo, under Suzukireaction conditions.

Compounds of formula 1 can be prepared by methods known in the art. Somesuch methods are illustrated and described below.

Synthesis from 2-halobenzamides

Treatment of a compound of formula 2 where X is halo such as chloro andother groups are as defined in Summary or a precursor group thereof,with an amine of formula R¹NH₂ where R¹ is as defined in Summary or aprecursor group thereof in the presence of an inorganic based such aspotassium carbonate, cesium carbonate and the like, and copper providesa compound of formula 3. Compounds of formula 2 are either commerciallyavailable or can be made by methods well known in the art. Compounds offormula 2 are converted to compounds of formula 1 by treatment with abase such as sodium hydride in the presence of N,N-carbonyldiimidazoleunder conditions well known in the art.

Alternatively, compounds of formula 1 from compound 2 can be prepared asshown in Method b below.

Treatment of a compound of formula 2 where X is halo, preferably chloroand other groups are as defined in Summary or a precursor group thereof,with an amine of formula R¹NH₂ in the presence of oxalyl chloride in anchlorinated organic solvent or an isocyanate of formula R¹NCO where R¹is as defined in Summary or a precursor group thereof provides anacylurea compound of formula 4 which is then cyclized to provide acompound of formula 1 in the presence of a base such as sodium hydrideor KHMDS, and the like under conditions well known in the art.

Synthesis from 2-halobenzoic Acids

Treatment of a benzoic acid compound of formula 5 where X is halo,preferably chloro and other groups are as defined in Summary or aprecursor group thereof, with an amine of formula R¹NH₂ where R¹ is asdefined in Summary or a precursor group thereof in the presence of aninorganic based such as potassium carbonate, cesium carbonate and thelike, and copper provides a compound of formula 6. Alternatively, theamination reaction can be carried out in the presence of LDA in THF at−78° C. Compounds of formula 5 are either commercially available or canbe made by methods well known in the art. Compounds of formula 6 areconverted to compounds of formula 1 by treatment with urea underconditions well known in the art.

Alternatively, compounds of formula 6 can be converted to amidocompounds of formula 3 by treating 6 with HATU or EDCI/HOBt and ammoniumchloride in the presence of an organic base such asdiisopropylethylamine in an organic solvent such as THF and the like.Compound 6 is then converted to a compound 1 can be prepared as shown inMethod a or method b above.

Synthesis from 2-aminobenzoic Acids

Treatment of a 2-aminobenzoic acid compound of formula 7 where R³ to R⁶groups are as defined in Summary or a precursor group thereof, with ahalide of R¹Br where R^(t) is as defined in Summary or a precursor groupthereof in the presence of in the presence of copper acetate in and abase such as triethylamine, pyridine, and the like provides compound 6which can then be converted to a compound of formula 1 as describedabove.

Synthesis from 2-aminobenzamide

Treatment of a 2-aminobenamide compound of formula 8 where R³ to R⁶groups are as defined in Summary or a precursor group thereof, with aboronic acid of formula R¹B(OH)₂ where R¹ is as defined in Summary or aprecursor group thereof in the presence of in the presence of copper(I)chloride in the presence of a base such as triethylamine, pyridine, andthe like, provides a compound of formula 3 which can then be convertedto a compound of formula 1 as described above.

Compounds of Formula (I) and (II) and the subembodiments describedherein can be converted to other compounds of Formula (I) and (II)respectively, by methods well known in the art. For example, a compoundof Formula (I) or (II) where R⁵ is halo (a precursor group) can beconverted to a corresponding compound of Formula (I) or (II)respectively where R⁵ is methoxy by treating it with sodium methoxide inpresence of CuI in DMF. A compound of Formula (I) or (II) where R⁵ ishalo (a precursor group) can be converted to a corresponding compound ofFormula (I) or (II) respectively where R⁵ is cyano by treating it withzinc cyanide in presence of Pd catalyst such as Pd(PH₃)₄ in DMF. Acompound of Formula (I) where R⁵ is halo (a precursor group) can beconverted to a corresponding compound of Formula (I) where R⁵ istrifluoromethyl by treating it with methyl2,2-difluoro-2-(fluorosulfonyl)acetate in presence of CuI in DMF.

Utility

Overexpression of the enzyme MAT2A has been demonstrated to mediatecertain cancers. In an embodiment, the cancer is neuroblastoma,intestine carcinoma (such as rectum carcinoma, colon carcinoma,familiarly adenomatous polyposis carcinoma and hereditary non-polyposiscolorectal cancer), esophageal carcinoma, labial carcinoma, larynxcarcinoma, hypopharynx carcinoma, tongue carcinoma, salivary glandcarcinoma, gastric carcinoma, adenocarcinoma, medullary thyroidcarcinoma, papillary thyroid carcinoma, renal carcinoma, kidneyparenchym carcinoma, ovarian carcinoma, cervix carcinoma, uterine corpuscarcinoma, endometrium carcinoma, chorion carcinoma, pancreaticcarcinoma, prostate carcinoma, testis carcinoma, breast carcinoma,urinary carcinoma, melanoma, brain tumors (such as glioblastoma,astrocytoma, meningioma, medulloblastoma and peripheral neuroectodermaltumors), Hodgkin lymphoma, non-Hodgkin lymphoma, Burkitt lymphoma, acutelymphatic leukemia (ALL), chronic lymphatic leukemia (CLL), acutemyeloid leukemia (AML), chronic myeloid leukemia (CML), adult T-cellleukemia, hepatocellular carcinoma, gall bladder carcinoma, bronchialcarcinoma, small cell lung carcinoma, non-small cell lung carcinoma,multiple myeloma, basalioma, teratoma, retinoblastoma, choroideamelanoma, seminoma, rhabdomyo sarcoma, craniopharyngeoma, osteosarcoma,chondrosarcoma, myosarcoma, liposarcoma, fibrosarcoma, Ewing sarcoma andplasmocytoma.

In another embodiment, the cancer is lung cancer, non-small cell lung(NSLC) cancer, bronchioloalveolar cell lung cancer, bone cancer,pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous orintraocular melanoma, uterine cancer, ovarian cancer, rectal cancer,cancer of the anal region, stomach cancer, gastric cancer, colon cancer,breast cancer, uterine cancer, carcinoma of the fallopian tubes,carcinoma of the endometrium, carcinoma of the vagina, carcinoma of thevulva, cancer of the small intestine, cancer of the endocrine system,cancer of the thyroid gland, cancer of the parathyroid gland, cancer ofthe adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancerof the penis, prostate cancer, cancer of the bladder, cancer of thekidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis,mesothelioma, hepatocellular cancer, biliary cancer, chronic or acuteleukemia, lymphocytic lymphomas, neoplasms of the central nervous system(CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme,astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas.squamous cell carcinomas, pituitary adenomas, including refractoryversions of any of the above cancers, or a combination of one or more ofthe above cancers.

Methylthioadenosine phosphorylase (MTAP) is an enzyme found in allnormal tissues that catalyzes the conversion of methylthioadenosine(MTA) into adenine and 5-methylthio-ribose-1-phosphate. The adenine issalvaged to generate adenosine monophosphate, and the5-methylthioribose-1-phosphate is converted to methionine and formate.Because of this salvage pathway, MTA can serve as an alternative purinesource when de novo purine synthesis is blocked, e.g., withantimetabolites, such as L-alanosine.

Many human and murine malignant cells lack MTAP activity. MTAPdeficiency is not only found in tissue culture cells but the deficiencyis also present in primary leukemias, gliomas, melanomas, pancreaticcancers, non-small cell lung cancers (NSLC), bladder cancers,astrocytomas, osteosarcomas, head and neck cancers, myxoidchondrosarcomas, ovarian cancers, endometrial cancers, breast cancers,soft tissue sarcomas, non-Hodgkin lymphomas, and mesotheliomas. It hasbeen reported by K. Marjon et al., Cell Reports 15 (2016) 574-587,incorporated herein by reference, that proliferation of cancer cellsthat are MTAP null is inhibited by knocking down MAT2A expression withshRNA. An MTAP null cancer is a cancer in which the MTAP gene has beendeleted or lost or otherwise deactivated or a cancer in which the MTAPprotein has a reduced or impaired function.

Accordingly, in an embodiment of the present disclosure there isprovided a method for treating an MTAP null cancer in a patient whereinsaid cancer is characterized by a reduction or absence of MTAPexpression or absence of the MTAP gene or reduced function of MTAPprotein as compared to cancers where the MTAP gene is present and fullyfunctioning, said method comprising administering to the patient in needthereof a therapeutically effective amount of a compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA), or a subembodiment described herein ora pharmaceutically acceptable salt thereof. In another embodiment,provided is a method of treating an MTAP null cancer in a patientcomprising administering to the patient in need thereof an effectiveamount of a compound of Formula (I) (IA), (IA′), (II), (IIA), (IIA′), ora subembodiment described herein or a pharmaceutically acceptable saltthereof. In an embodiment, the MTAP null cancer is leukemia, glioma,melanoma, pancreatic, non-small cell lung cancer (NSLC), bladder cancer,astrocytoma, osteosarcoma, head and neck cancer, myxoid chondrosarcoma,ovarian cancer, endometrial cancer, breast cancer, soft tissue sarcoma,non-Hodgkin lymphoma or mesothelioma. In another embodiment, the MTAPnull cancer is pancreatic cancer. In yet another embodiment, the MTAPnull cancer is bladder cancer, melanoma, brain cancer, lung cancer,pancreatic cancer, breast cancer, esophageal cancer, head and neckcancer, kidney cancer, colon cancer, diffuse large B cell lymphoma(DLBCL), acute lymphoblastic leukemia (ALL) or mantle cell lymphoma(MCL). In yet another embodiment, the MT AP null cancer is gastriccancer. In yet another embodiment, the cancer is colon cancer. In yetanother embodiment, the MTAP null cancer is liver cancer. In yet anotherembodiment, the MTAP null cancer is glioblastoma multiforme (GBM). Inyet another embodiment, the MTAP mill cancer is bladder cancer. In yetanother embodiment, the MTAP null cancer is esophageal cancer. In yetanother embodiment, the MTAP null cancer is breast cancer. In yetanother embodiment, the MTAP null cancer is NSLCC. In yet anotherembodiment, the MTAP null cancer is MCL. In yet another embodiment, theMTAP null cancer is DLBCL. In yet another embodiment, the MTAP nullcancer is ALL.

Genomic analysis of MTAP null cell lines has shown that cell lines thatalso incorporate a. KRAS mutation or a. p53 mutation were sensitive toMAT2A inhibition. Accordingly, also provided is a method for treating acancer in a patient wherein said cancer is characterized by reduction orabsence of MTAP expression or absence of the MTAP gene or reducedfunction of MTAP protein (i.e., MTAP null) and further characterized bythe presence of mutant KRAS and/or mutant p53, said method comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA″), or asubembodiment described herein. In one embodiment, the cancer is MTAPnull and KRAS mutant. In another embodiment, the cancer is MTAP null andp53 mutant. In yet another embodiment, the cancer is MTAP null, KRASmutant and p53 mutant.

The term “mutant KRAS” or “KRAS mutation” refers to KRAS protein (orgene encoding said protein) incorporating an activating mutation thatalters its normal function. For example, a mutant KRAS protein mayincorporate a single amino acid substitution at position 12 or 13. In aparticular embodiment, the KRAS mutant incorporates a G12× or G13×substitution, wherein X represents any amino acid change at theindicated position. In a particular embodiment, the substitution isG12V, G12R, G12C or G13D. In another embodiment, the substitution isG13D. By “mutant p53” or “p53 mutation” is meant p53 protein (or geneencoding said protein) incorporating a mutation that inhibits oreliminates its tumor suppressor function. In an embodiment, said p53mutation is, Y126_splice, K132Q, M133K, R174fs, R175H, R196*, C238S,C242Y, G245S, R248W, R248Q, I255T, D259V, S261_splice, R267P, R273C,R282W, A159V or R280K. In an embodiment, the foregoing cancer isnon-small cell lung cancer (NSLCC), pancreatic cancer, head and neckcancer, gastric cancer, breast cancer, colon cancer or ovarian cancer.

Assay

The ability of compounds of the disclosure to inhibit MAT2A can bemeasured as described in Biological Example 1 below.

Pharmaceutical Composition

The compounds of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a pharmaceutically acceptable saltthereof, may be in the form of compositions suitable for administrationto a subject. In general, such compositions are pharmaceuticalcompositions comprising a compound of Formula (I), (IA), (IA′), (II),(IIA), (IIA′), or a subembodiment described herein or a pharmaceuticallyacceptable salt thereof and one or more pharmaceutically acceptable orphysiologically acceptable excipients. In certain embodiments, thecompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a pharmaceutically acceptable saltthereof is present in a therapeutically effective amount. Thepharmaceutical compositions may be used in the methods disclosed herein;thus, for example, the pharmaceutical compositions can be administeredex vivo or in vivo to a subject in order to practice the therapeuticmethods and uses described herein.

The pharmaceutical compositions can be formulated to be compatible withthe intended method or route of administration; exemplary routes ofadministration are set forth herein. Furthermore, the pharmaceuticalcompositions may be used in combination with other therapeuticallyactive agents or compounds as described herein in order to treat thediseases, disorders and conditions contemplated by the presentdisclosure.

The pharmaceutical compositions containing the active ingredient (e.g.,a compound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, a pharmaceutically acceptable saltthereof) may be in a form suitable for oral use, for example, astablets, capsules, troches, lozenges, aqueous or oily suspensions,dispersible powders or granules, emulsions, hard or soft capsules, orsyrups, solutions, microbeads or elixirs. Pharmaceutical compositionsintended for oral use may be prepared according to any method known tothe art for the manufacture of pharmaceutical compositions, and suchcompositions may contain one or more agents such as, for example,sweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets, capsules and the like contain the activeingredient in admixture with non-toxic pharmaceutically acceptableexcipients which are suitable for the manufacture of tablets, capsules,and the like. These excipients may be, for example, diluents, such ascalcium carbonate, sodium carbonate, lactose, calcium phosphate orsodium phosphate; granulating and disintegrating agents, for example,corn starch, or alginic acid; binding agents, for example starch,gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc.

The tablets, capsules and the like suitable for oral administration maybe uncoated or coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction. For example, a time-delay material such as glyceryl monostearateor glyceryl di-stearate may be employed. The tablets may also be coatedby techniques known in the art to form osmotic therapeutic tablets forcontrolled release. Additional agents include biodegradable orbiocompatible particles or a polymeric substance such as polyesters,polyamine acids, hydrogel, polyvinyl pyrrolidone, polyanhydrides,polyglycolic acid, ethylene-vinyl acetate, methylcellulose,carboxymethylcellulose, protamine sulfate, or lactide and glycolidecopolymers, polylactide and glycolide copolymers, or ethylene vinylacetate copolymers in order to control delivery of an administeredcomposition. For example, the oral agent can be entrapped inmicrocapsules prepared by coacervation techniques or by interfacialpolymerization, by the use of hydroxymethyl cellulose orgelatin-microcapsules or poly (methyl methacrylate) microcapsules,respectively, or in a colloid drug delivery system. Colloidal dispersionsystems include macromolecule complexes, nanocapsules, microspheres,microbeads, and lipid-based systems, including oil-in-water emulsions,micelles, mixed micelles, and liposomes. Methods for the preparation ofthe above-mentioned formulations are known in the art.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate, kaolin ormicrocrystalline cellulose, or as soft gelatin capsules wherein theactive ingredient is mixed with water or an oil medium, for examplepeanut oil, liquid paraffin, or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture thereof. Such excipients can besuspending agents, for example sodium carboxymethylcellulose,methylcellulose, (hydroxypropyl)methyl cellulose, sodium alginate,polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents, for example a naturally-occurring phosphatide (e.g.,lecithin), or condensation products of an alkylene oxide with fattyacids (e.g., poly-oxyethylene stearate), or condensation products ofethylene oxide with long chain aliphatic alcohols (e.g., forheptdecaethyleneoxycetanol), or condensation products of ethylene oxidewith partial esters derived from fatty acids and a hexitol (e.g.,polyoxyethylene sorbitol monooleate), or condensation products ofethylene oxide with partial esters derived from fatty acids and hexitolanhydrides (e.g., polyethylene sorbitan monooleate). The aqueoussuspensions may also contain one or more preservatives.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified herein.

The pharmaceutical compositions may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example olive oilor arachis oil, or a mineral oil, for example, liquid paraffin, ormixtures of these. Suitable emulsifying agents may be naturallyoccurring gums, for example, gum acacia or gum tragacanth; naturallyoccurring phosphatides, for example, soy bean, lecithin, and esters orpartial esters derived from fatty acids; hexitol anhydrides, forexample, sorbitan monooleate; and condensation products of partialesters with ethylene oxide, for example, polyoxyethylene sorbitanmonooleate.

The pharmaceutical compositions typically comprise a therapeuticallyeffective amount of a compound of Formula (I), (IA), (IA′), (II), (IIA),(IIA′), or a subembodiment described herein, or a salt thereof, and oneor more pharmaceutically acceptable excipient. Suitable pharmaceuticallyacceptable excipients include, but are not limited to, antioxidants(e.g., ascorbic acid and sodium bisulfate), preservatives (e.g., benzylalcohol, methyl parabens, ethyl or n-propyl, p-hydroxybenzoate),emulsifying agents, suspending agents, dispersing agents, solvents,fillers, bulking agents, detergents, buffers, vehicles, diluents, and/oradjuvants. For example, a suitable vehicle may be physiological salinesolution or citrate buffered saline, possibly supplemented with othermaterials common in pharmaceutical compositions for parenteraladministration. Neutral buffered saline or saline mixed with serumalbumin are further exemplary vehicles. Those skilled in the art willreadily recognize a variety of buffers that can be used in thepharmaceutical compositions and dosage forms contemplated herein.Typical buffers include, but are not limited to, pharmaceuticallyacceptable weak acids, weak bases, or mixtures thereof. As an example,the buffer components can be water soluble materials such as phosphoricacid, tartaric acids, lactic acid, succinic acid, citric acid, aceticacid, ascorbic acid, aspartic acid, glutamic acid, and salts thereof.Acceptable buffering agents include, for example, a Tris buffer,N-(2-Hydroxyethyl)piperazine-N′-(2-ethanesulfonic acid) (HEPES),2-(N-Morpholino)ethanesulfonic acid (MES),2-(N-Morpholino)ethanesulfonic acid sodium salt (MES),3-(N-Morpholino)propanesulfonic acid (MOPS), andN-tris[Hydroxymethyl]methyl-3-aminopropanesulfonic acid (TAPS).

After a pharmaceutical composition has been formulated, it may be storedin sterile vials as a solution, suspension, gel, emulsion, solid, ordehydrated or lyophilized powder. Such formulations may be stored eitherin a ready-to-use form, a lyophilized form requiring reconstitutionprior to use, a liquid form requiring dilution prior to use, or otheracceptable form. In some embodiments, the pharmaceutical composition isprovided in a single-use container (e.g., a single-use vial, ampoule,syringe, or autoinjector (similar to, e.g., an EpiPen®)), whereas amulti-use container (e.g., a multi-use vial) is provided in otherembodiments.

Formulations can also include carriers to protect the compositionagainst rapid degradation or elimination from the body, such as acontrolled release formulation, including liposomes, hydrogels, prodrugsand microencapsulated delivery systems. For example, a time delaymaterial such as glyceryl monostearate or glyceryl stearate alone, or incombination with a wax, may be employed. Any drug delivery apparatus maybe used to deliver a compound of Formula (I), (IA), (IA′), (II), (IIA),(IIA′), or a subembodiment described herein, or a salt thereof,including implants (e.g., implantable pumps) and catheter systems, slowinjection pumps and devices, all of which are well known to the skilledartisan.

Depot injections, which are generally administered subcutaneously orintramuscularly, may also be utilized to release the compound of Formula(I), (IA), (IA′), (II), (IIA), (IIA′), or a subembodiment describedherein, or a salt thereof over a defined period of time. Depotinjections are usually either solid- or oil-based and generally compriseat least one of the formulation components set forth herein. One ofordinary skill in the art is familiar with possible formulations anduses of depot injections.

The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleagenous suspension. The suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents mentioned herein. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Acceptable diluents,solvents and dispersion media that may be employed include water,Ringer's solution, isotonic sodium chloride solution, Cremophor EL™(BASF, Parsippany, N.J.) or phosphate buffered saline (PBS), ethanol,polyol (e.g., glycerol, propylene glycol, and liquid polyethyleneglycol), and suitable mixtures thereof. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose, any bland fixed oil may be employed, including synthetic mono-or diglycerides. Moreover, fatty acids such as oleic acid, find use inthe preparation of injectables. Prolonged absorption of particularinjectable formulations can be achieved by including an agent thatdelays absorption (e.g., aluminum monostearate or gelatin).

A compound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof may also beadministered in the form of suppositories for rectal administration orsprays for nasal or inhalation use. The suppositories can be prepared bymixing the drug with a suitable non-irritating excipient which is solidat ordinary temperatures but liquid at the rectal temperature and willtherefore melt in the rectum to release the drug. Such materialsinclude, but are not limited to, cocoa butter and polyethylene glycols.

Routes of Administration

Compounds of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof and compositionscontaining the same may be administered in any appropriate manner.Suitable routes of administration include oral, parenteral (e.g.,intramuscular, intravenous, subcutaneous (e.g., injection or implant),intraperitoneal, intracisternal, intraarticular, intraperitoneal,intracerebral (intraparenchymal) and intracerebroventricular), nasal,vaginal, sublingual, intraocular, rectal, topical (e.g., transdermal),buccal and inhalation. Depot injections, which are generallyadministered subcutaneously or intramuscularly, may also be utilized toadminister the compounds of Formula (I), (IA), (IA′), (II), (IIA),(IIA′), or a subembodiment described herein, or a salt thereof over adefined period of time. Particular embodiments of the present inventioncontemplate oral administration.

Combination Therapy

The present invention contemplates the use of compounds of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof in combination with one or more active therapeuticagents (e.g., chemotherapeutic agents) or other prophylactic ortherapeutic modalities (e.g., radiation). In such combination therapy,the various active agents frequently have different, complementarymechanisms of action. Such combination therapy may be especiallyadvantageous by allowing a dose reduction of one or more of the agents,thereby reducing or eliminating the adverse effects associated with oneor more of the agents. Furthermore, such combination therapy may have asynergistic therapeutic or prophylactic effect on the underlyingdisease, disorder, or condition.

As used herein, “combination” is meant to include therapies that can beadministered separately, for example, formulated separately for separateadministration (e.g., as may be provided in a kit), and therapies thatcan be administered together in a single formulation (i.e., a“co-formulation”).

In certain embodiments, the compounds of Formula (I), (IA), (IA′), (II),(IIA), (IIA′), or a subembodiment described herein, or a salt thereofare administered or applied sequentially, e.g., where one agent isadministered prior to one or more other agents. In other embodiments,the compounds of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof are administeredsimultaneously, e.g., where two or more agents are administered at orabout the same time; the two or more agents may be present in two ormore separate formulations or combined into a single formulation (i.e.,a co-formulation). Regardless of whether the two or more agents areadministered sequentially or simultaneously, they are considered to beadministered in combination for purposes of the present disclosure.

The compounds of (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof may be used incombination with at least one other (active) agent in any mannerappropriate under the circumstances. In one embodiment, treatment withthe at least one active agent and at least one compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof is maintained over a period of time. In anotherembodiment, treatment with the at least one active agent is reduced ordiscontinued (e.g., when the subject is stable), while treatment withthe compound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof is maintained at aconstant dosing regimen. In a further embodiment, treatment with the atleast one active agent is reduced or discontinued (e.g., when thesubject is stable), while treatment with a compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof is reduced (e.g., lower dose, less frequent dosing orshorter treatment regimen). In yet another embodiment, treatment withthe at least one active agent is reduced or discontinued (e.g., when thesubject is stable), and treatment with the compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof is increased (e.g., higher dose, more frequent dosingor longer treatment regimen). In yet another embodiment, treatment withthe at least one active agent is maintained and treatment with thecompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof is reduced ordiscontinued (e.g., lower dose, less frequent dosing or shortertreatment regimen). In yet another embodiment, treatment with the atleast one active agent and treatment with the compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof are reduced or discontinued (e.g., lower dose, lessfrequent dosing or shorter treatment regimen).

The present disclosure provides methods for treating cancer with acompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof and at least oneadditional therapeutic or diagnostic agent.

In some embodiments, the compound of Formula (I), (IA), (IA′), (II),(IIA), (IIA′), or a subembodiment described herein, or a salt thereof isadministered in combination with at least one additional therapeuticagent, selected from Temozolomide, Pemetrexed, Pegylated liposomaldoxorubicin (Doxil), Eribulin (Halaven), Ixabepilone (Ixempra),Protein-bound paclitaxel (Abraxane), Oxaliplatin, Irinotecan, Venatoclax(bcl2 inhibitor), 5-azacytadine, Anti-CD20 therapeutics, such as Rituxanand obinutuzumab, Hormonal agents (anastrozole, exemestand, letrozole,zoladex, lupon eligard), CDK4/6 inhibitors, Palbociclib, Abemaciclib,CPI (Avelumab, Cemiplimab-rwlc, and Bevacizumab.

In certain embodiments, the present disclosure provides methods fortreating cancer comprising administration of a compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof in combination with a signal transduction inhibitor(STI) to achieve additive or synergistic suppression of tumor growth. Asused herein, the term “signal transduction inhibitor” refers to an agentthat selectively inhibits one or more steps in a signaling pathway.Examples of signal transduction inhibitors (STIs) useful in methodsdescribed herein include, but are not limited to: (i) bcr/abl kinaseinhibitors (e.g., GLEEVEC); (ii) epidermal growth factor (EGF) receptorinhibitors, including kinase inhibitors and antibodies; (iii) her-2/neureceptor inhibitors (e.g., HERCEPTIN); (iv) inhibitors of Akt familykinases or the Akt pathway (e.g., rapamycin); (v) cell cycle kinaseinhibitors (e.g., flavopiridol); and (vi) phosphatidyl inositol kinaseinhibitors. Agents involved in immunomodulation can also be used incombination with one or more compounds of Formula (I), (IA), (IA′),(II), (IIA), (IIA′), or a subembodiment described herein, or a saltthereof for the suppression of tumor growth in cancer patients.

In certain embodiments, the present disclosure provides methods fortreating cancer comprising administration of a compound of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof in combination with a chemotherapeutic agents.Examples of chemotherapeutic agents include, but are not limited to,alkylating agents such as thiotepa and cyclosphosphamide; alkylsulfonates such as busulfan, improsulfan and piposulfan; aziridines suchas benzodopa, carboquone, meturedopa, and uredopa; ethylenimines andmethylamelamines including altretamine, triethylenemelamine,trietylenephosphoramide, triethylenethiophosphaoramide andtrimethylolomelamime; nitrogen mustards such as chiorambucil,chlomaphazine, cholophosphamide, estramustine, ifosfamide,mechlorethamine, mechlorethamine oxide hydrochloride, melphalan,novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard;nitrosureas such as carmustine, chlorozotocin, fotemustine, lomustine,nimustine, ranimustine; antibiotics such as aclacinomysins, actinomycin,authramycin, azaserine, bleomycins, cactinomycin, calicheamicin,carabicin, caminomycin, carzinophilin, chromomycins, dactinomycin,daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin,epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins,mycophenolic acid, nogalamycin, olivomycins, peplomycin, potfiromycin,puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin,tubercidin, ubenimex, zinostatin, zorubicin; anti-metabolites such asmethotrexate and 5-fluorouracil (5-FU); folic acid analogs such asdenopterin, methotrexate, pteropterin, trimetrexate; purine analogs suchas fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidineanalogs such as ancitabine, azacitidine, 6-azauridine, carmofur,cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine,5-FU; androgens such as calusterone, dromostanolone propionate,epitiostanol, mepitiostane, testolactone; anti-adrenals such asaminoglutethimide, mitotane, trilostane; folic acid replenisher such asfrolinic acid; aceglatone; aldophosphamide glycoside; aminolevulinicacid; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine;demecolcine; diaziquone; elformithine; elliptinium acetate; etoglucid;gallium nitrate; hydroxyurea; lentinan; lonidamine; mitoguazone;mitoxantrone; mopidamol; nitracrine; pentostatin; phenamet; pirarubicin;podophyllinic acid; 2-ethylhydrazide; procarbazine; razoxane; sizofiran;spirogermanium; tenuazonic acid; triaziquone;2,2′,2″-trichlorotriethylamine; urethan; vindesine; dacarbazine;mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine;arabinoside (Ara-C); cyclophosphamide; thiotepa; taxoids, e.g.,paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine;mercaptopurine; methotrexate; platinum and platinum coordinationcomplexes such as cisplatin and carboplatin; vinblastine; etoposide(VP-16); ifosfamide; mitomycin C; mitoxantrone; vincristine;vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin;xeloda; ibandronate; CPT11; topoisomerase inhibitors;difluoromethylomithine (DMFO); retinoic acid; esperamicins;capecitabine; and pharmaceutically acceptable salts, acids orderivatives of any of the above. In a particular embodiment, compoundsof the present disclosure are coadministered with a cytostatic compoundselected from the group consisting of cisplatin, doxorubicin, taxol,taxotere and mitomycin C. In a particular embodiment, the cytostaticcompound is doxorubicin.

Chemotherapeutic agents also include anti-hormonal agents that act toregulate or inhibit hormonal action on tumors such as anti-estrogens,including for example tamoxifen, raloxifene, aromatase inhibiting4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, onapristone,and toremifene; and antiandrogens such as flutamide, nilutamide,bicalutamide, enzalutamide, apalutamide, abiraterone acetate,leuprolide, and goserelin; and pharmaceutically acceptable salts, acidsor derivatives of any of the above. In certain embodiments, combinationtherapy comprises administration of a hormone or related hormonal agent.

The present disclosure also contemplates the use of the compounds ofFormula (I), (IA), (IA′), (II), (IIA), (IIA′), or a subembodimentdescribed herein, or a salt thereof in combination with immunecheckpoint inhibitors. The tremendous number of genetic and epigeneticalterations that are characteristic of all cancers provides a diverseset of antigens that the immune system can use to distinguish tumorcells from their normal counterparts. In the case of T cells, theultimate amplitude (e.g., levels of cytokine production orproliferation) and quality (e.g., the type of immune response generated,such as the pattern of cytokine production) of the response, which isinitiated through antigen recognition by the T-cell receptor (TCR), isregulated by a balance between co-stimulatory and inhibitory signals(immune checkpoints). Under normal physiological conditions, immunecheckpoints are crucial for the prevention of autoimmunity (i.e., themaintenance of self-tolerance) and also for the protection of tissuesfrom damage when the immune system is responding to pathogenicinfection. The expression of immune checkpoint proteins can bedysregulated by tumors as an important immune resistance mechanism.Examples of immune checkpoint inhibitors include but are not limited toCTLA-4, PD-1, PD-L1, BTLA, TIM3, LAG3, OX40, 41BB, VISTA, CD96, TGFβ,CD73, CD39, A2AR, A2BR, IDO1, TDO2, Arginase, B7-H3, B7-H4. Cell-basedmodulators of anti-cancer immunity are also contemplated. Examples ofsuch modulators include but are not limited to chimeric antigen receptorT-cells, tumor infiltrating T-cells and dendritic-cells.

The present disclosure contemplates the use of compounds of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof in combination with inhibitors of the aforementionedimmune-checkpoint receptors and ligands, for example ipilimumab,abatacept, nivolumab, pembrolizumab, atezolizumab, nivolumab, anddurvalumab.

Additional treatment modalities that may be used in combination with acompound of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof include radiotherapy,a monoclonal antibody against a tumor antigen, a complex of a monoclonalantibody and toxin, a T-cell adjuvant, bone marrow transplant, orantigen presenting cells (e.g., dendritic cell therapy).

The present disclosure contemplates the use of compounds of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof for the treatment of glioblastoma either alone or incombination with radiation and/or temozolomide (TMZ), avastin orlomustine.

The present disclosure encompasses pharmaceutically acceptable salts,acids or derivatives of any of the above.

Dosing

The compounds of Formula (I), (IA), (IA′), (II), (IIA), (IIA′), or asubembodiment described herein, or a salt thereof may be administered toa subject in an amount that is dependent upon, for example, the goal ofadministration (e.g., the degree of resolution desired); the age,weight, sex, and health and physical condition of the subject to whichthe formulation is being administered; the route of administration; andthe nature of the disease, disorder, condition or symptom thereof. Thedosing regimen may also take into consideration the existence, nature,and extent of any adverse effects associated with the agent(s) beingadministered. Effective dosage amounts and dosage regimens can readilybe determined from, for example, safety and dose-escalation trials, invivo studies (e.g., animal models), and other methods known to theskilled artisan.

In general, dosing parameters dictate that the dosage amount be lessthan an amount that could be irreversibly toxic to the subject (themaximum tolerated dose (MTD)) and not less than an amount required toproduce a measurable effect on the subject. Such amounts are determinedby, for example, the pharmacokinetic and pharmacodynamic parametersassociated with ADME, taking into consideration the route ofadministration and other factors.

An effective dose (ED) is the dose or amount of an agent that produces atherapeutic response or desired effect in some fraction of the subjectstaking it. The “median effective dose” or ED₅₀ of an agent is the doseor amount of an agent that produces a therapeutic response or desiredeffect in 50% of the population to which it is administered. Althoughthe ED₅₀ is commonly used as a measure of reasonable expectance of anagent's effect, it is not necessarily the dose that a clinician mightdeem appropriate taking into consideration all relevant factors. Thus,in some situations the effective amount is more than the calculatedED₅₀, in other situations the effective amount is less than thecalculated ED₅₀, and in still other situations the effective amount isthe same as the calculated ED₅₀.

In addition, an effective dose of a compound of Formula (I), (IA),(IA′), (II), (IIA), (IIA′), or a subembodiment described herein, or asalt thereof may be an amount that, when administered in one or moredoses to a subject, produces a desired result relative to a healthysubject. For example, for a subject experiencing a particular disorder,an effective dose may be one that improves a diagnostic parameter,measure, marker and the like of that disorder by at least about 5%, atleast about 10%, at least about 20%, at least about 25%, at least about30%, at least about 40%, at least about 50%, at least about 60%, atleast about 70%, at least about 80%, at least about 90%, or more than90%, where 100% is defined as the diagnostic parameter, measure, markerand the like exhibited by a normal subject.

In certain embodiments, the compounds of (I), (IA), (IA′), (II), (IIA),(IIA′), or a subembodiment described herein, or a salt thereof may beadministered (e.g., orally) at dosage levels of about 0.01 mg/kg toabout 50 mg/kg, or about 1 mg/kg to about 25 mg/kg, of subject bodyweight per day, one or more times a day, to obtain the desiredtherapeutic effect.

For administration of an oral agent, the compositions can be provided inthe form of tablets, capsules and the like containing from 1.0 to 1000milligrams of the active ingredient, particularly 1.0, 3.0, 5.0, 10.0,15.0, 20.0, 25.0, 50.0, 75.0, 100.0, 150.0, 200.0, 250.0, 300.0, 400.0,500.0, 600.0, 750.0, 800.0, 900.0, and 1000.0 milligrams of the activeingredient.

In certain embodiments, the dosage of the compound of Formula (I), (IA),(IA′), (II), (IIA), (IIA′), or a subembodiment described herein, or asalt thereof is contained in a “unit dosage form”. The phrase “unitdosage form” refers to physically discrete units, each unit containing apredetermined amount of the compound of Formula (I), (IA), (IA′), (II),(IIA), (IIA′), or a subembodiment described herein, or a salt thereof,either alone or in combination with one or more additional agents,sufficient to produce the desired effect. It will be appreciated thatthe parameters of a unit dosage form will depend on the particular agentand the effect to be achieved.

Kits

The present invention also contemplates kits comprising a compound ofFormula (I), (IA), (IA′), (II), (IIA), (IIA′), or a subembodimentdescribed herein, or a salt thereof, and pharmaceutical compositionsthereof. The kits are generally in the form of a physical structurehousing various components, as described below, and may be utilized, forexample, in practicing the methods described above.

A kit can include one or more of the compound of Formula (I), (IA),(IA′), (II), (IIA), (IIA′), or a subembodiment described herein, or asalt thereof (provided in, e.g., a sterile container), which may be inthe form of a pharmaceutical composition suitable for administration toa subject. The compound of Formula (I), (IA), (IA′), (II), (IIA),(IIA′), or a subembodiment described herein, or a salt thereof can beprovided in a form that is ready for use (e.g., a tablet or capsule) orin a form requiring, for example, reconstitution or dilution (e.g., apowder) prior to administration. When the compounds of Formula (I),(IA), (IA′), (II), (IIA), (IIA′), or a subembodiment described herein,or a salt thereof are in a form that needs to be reconstituted ordiluted by a user, the kit may also include diluents (e.g., sterilewater), buffers, pharmaceutically acceptable excipients, and the like,packaged with or separately from the compounds of Formula (I), (IA),(IA′), (II), (IIA), (IIA′), or a subembodiment described herein, for asalt thereof. When combination therapy is contemplated, the kit maycontain the several agents separately or they may already be combined inthe kit. Each component of the kit may be enclosed within an individualcontainer, and all of the various containers may be within a singlepackage. A kit of the present invention may be designed for conditionsnecessary to properly maintain the components housed therein (e.g.,refrigeration or freezing).

A kit may contain a label or packaging insert including identifyinginformation for the components therein and instructions for their use(e.g., dosing parameters, clinical pharmacology of the activeingredient(s), including mechanism of action, pharmacokinetics andpharmacodynamics, adverse effects, contraindications, etc.). Labels orinserts can include manufacturer information such as lot numbers andexpiration dates. The label or packaging insert may be, e.g., integratedinto the physical structure housing the components, contained separatelywithin the physical structure, or affixed to a component of the kit(e.g., an ampule, tube or vial).

Labels or inserts can additionally include, or be incorporated into, acomputer readable medium, such as a disk (e.g., hard disk, card, memorydisk), optical disk such as CD- or DVD-ROM/RAM, DVD, MP3, magnetic tape,or an electrical storage media such as RAM and ROM or hybrids of thesesuch as magnetic/optical storage media, FLASH media or memory-typecards. In some embodiments, the actual instructions are not present inthe kit, but means for obtaining the instructions from a remote source,e.g., via the internet, are provided.

EXAMPLES

The following examples and references (intermediates) are put forth soas to provide those of ordinary skill in the art with a completedisclosure and description of how to make and use the present invention,and are not intended to limit the scope of what the inventors regard astheir invention, nor are they intended to represent that the experimentsbelow were performed or that they are all of the experiments that may beperformed. It is to be understood that exemplary descriptions written inthe present tense were not necessarily performed, but rather that thedescriptions can be performed to generate data and the like of a naturedescribed therein. Efforts have been made to ensure accuracy withrespect to numbers used (e.g., amounts, temperature, etc.), but someexperimental errors and deviations should be accounted for.

Unless indicated otherwise, parts are parts by weight, molecular weightis weight average molecular weight, temperature is in degrees Celsius (°C.), and pressure is at or near atmospheric. Standard abbreviations areused, including the following: μg=microgram; μl or μL=microliter;mM=millimolar; μM=micromolar; aa=amino acid(s); Ac₂O=acetic anhydride;AcCl=acetylchloride; ACN=acetonitrile;AIBN=2,2′-Azobis(2-methylpropionitrile); BID=twice daily;BINAP=2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Boc₂O or(Boc)₂O=di-tert-butyl dicarbonate; bp=base pair(s); BSA=bovine serumalbumin; BW=body weight; d=doublet; dd=doublet of doublets; DEAD=diethylazodicarboxylate; DIBAL=diisobutylaluminium hydrideDIEA=N,N-diisopropylethylamine; DIPEA=N,N-diisopropylethylamine; dl ordL=deciliter; DMA=dimethylacetamide; DMAP=dimethylaminopyridine;DME=1,2-dimethoxyethane; DMEM=Dulbeco's Modification of Eagle's Medium;DMF=N,N-dimethylformamide; DMSO=dimethylsulfoxide;dppf=1,1′-Bis(diphenylphosphino)ferrocene; DTT=dithiothreitol;EDTA=ethylenediaminetetraacetic acid; ES=electrospray; EtOAc=ethylacetate; EtOH=ethanol; g=gram; h or hr=hour(s);HATU=2-(1H-7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate;HEPES=4-(2-hydroxyethyl)-1-piperazineethylanesulfonic acid; HOAc=aceticacid; HPLC=high performance liquid chromatography; HPLC=high pressureliquid chromatography; i.m.=intramuscular(ly); i.p.=intraperitoneal(ly);IHC=immunohistochemistry; IPA=isopropyl alcohol; kb=kilobase(s);kDa=kilodalton; kg=kilogram; l or L=liter; LC=liquid chromatography;LCMS=liquid chromatography and mass spectrometry; m/z=mass to chargeratio; M=molar; m=multiplet; MeCN=acetonitrile; MeOH=methanol;MeSO₂Cl=methanesulfonylchloride; mg=milligram; min=minute(s);min=minutes; ml or mL=milliliter; mM=millimolar; MS=mass spectrometry;MsCl=methanesulfonylchloride; N=normal; NADPH=nicotinamide adeninedinucleotide phosphate; NBS=N-bromosuccinamide; ng=nanogram;nm=nanometer; nM=nanomolar; NMP=N-methylpyrrolidone; NMR=nuclearmagnetic resonance; ns=not statistically significant; nt=nucleotides(s);PBS=phosphate-buffered saline; Pd/C=palladium on carbon;Pd₂(dba)₃=Tris(debenzylideneactone) dipalladium;Pd(dppf)Cl₂=1,1′-bis(diphenylphosphino)ferrocene-palladium(ll)dichloride;PE=petroleum ether; QD=daily; QM=monthly; QW=weekly; rac=racemic;Rt=retention time; s=singlet; s or sec=second(s); sat.=saturated; SC orSQ=subcutaneous(ly); t=triplet; TBAB=tetra-n-butylammonium bromide;TEA=triethylamine; TFA=trifluoroacetic acid; THF=tetrahydrofuran;TLC=thin layer chromatography; TMSCl=trimethylsilylchloride;TsOH=p-toluenesulfonic acid; U=unit; wt=wildtype.

SYNTHETIC EXAMPLES Reference 1 Synthesis of7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

Step 1: Synthesis of 4-chloro-2-(phenylamino)benzoic Acid

To a stirred solution of 2,4-dichlorobenzoic acid (1 equiv) in DMF (0.5M) were added aniline (1.5 equiv), copper(0) powder (0.5 equiv) andpotassium carbonate (2 equiv) and the reaction mixture was stirred at150° C. for 5 h. After completion of reaction, the reaction mixture wasbrought to room temperature and filtered through a Celite pad. Theobtained filtrate was acidified with 2 N HCl. The solid formed wasfiltered and dried under vacuum to provide4-chloro-2-(phenylamino)benzoic acid as brown solid.

Step 2: Synthesis of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one

A mixture of 4-chloro-2-(phenylamino)benzoic acid (1 equiv) and urea (5equiv) was charged in a round bottom flask equipped with a stir bar andheated at 200° C. for 2 h. The crude was poured into water and extractedwith EtOAc. The combined organic layers were separated, dried overanhydrous sodium sulfate, filtered and concentrated under reducedpressure to afford crude product. The crude was purified by columnchromatography (20-30% EtOAc/Hexane) to provide the title compound as ayellow solid. ¹H NMR (400 MHz, DMSO-d₆): δ=11.82 (s, 1H), 8.04 (d, J=8.3Hz, 1H), 7.66-7.56 (m, 3H), 7.48-7.44 (m, 2H), 7.31 (dd, J=8.3, 1.9 Hz,1H), 6.31 (d, J=1.8 Hz, 1H). m/z [M+H]⁺ 273.18

Reference 2 Synthesis of7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-chloro-2-(pyridin-3-ylamino)benzamide

To a stirred solution of 2,4-dichlorobenzamide (1 equiv) in DMF (0.5 M)were added 3-aminopyridine (1.5 equiv), copper(0) powder (0.5 equiv) andpotassium carbonate (2 equiv) and the reaction mixture was stirred at150° C. for 5 h. After completion of reaction, the reaction mixture wasbrought to room temperature and filtered through a Celite pad. Theobtained filtrate was acidified with 2 N HCl. The solid formed wasfiltered and dried under vacuum to provide the title compound as a brownsolid. m/z [M+H]⁺ 249.1

Step 2: Synthesis of7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione

A vial was charged with 4-chloro-2-(pyridin-3-ylamino)benzamide (1.0equiv) and DMF (0.2 M). To the reaction vessel at 0° C. was added NaH(60% in mineral oil, 3.0 equiv) and the reaction mixture was stirred atroom temperature for 10 min. To the vessel was added CDI (1.5 equiv) andthe reaction mixture was stirred at room temperature for 20 min. Thereaction was quenched by the addition of MeOH (0.5 mL) and AcOH (0.2mL). The crude reaction mixture was directly purified by reverse phasecolumn chromatography (20-75% MeCN/water, 0.1% formic acid). ¹H NMR (400MHz, DMSO-d₆) δ 11.82 (s, 1H), 8.69 (d, J=4.9 Hz, 1H), 8.61 (s, 1H),7.99 (d, J=8.4 Hz, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.68-7.50 (m, 1H), 7.27(d, J=8.6 Hz, 1H), 6.32 (s, 1H). m/z [M+H]⁺ 274.0

Proceeding as described in Reference 2, Step 1,2-((2-chlorophenyl)amino)-6-cyclopropyl-nicotinamide was prepared byusing 2-chloro aniline and 2-chloro-6-cyclopropylnicotinamide instead of3-aminopyridine and 2,4-dichlorobenzamide respectively.

Proceeding as described in Step 2 above, the following compounds wereprepared:

7-Chloro-1-(pyridin-4-yl)quinazoline-2,4(1H,3H)-dione was prepared using4-chloro-2-(pyridin-4-ylamino)benzamide

1-(2-Chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared using 2-((2-chlorophenyl)amino)-6-cyclopropylnicotinamide.

1-(2-Bromophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared using2-((2-bromophenyl)amino)-6-(trifluoromethyl)nicotinamide.

1-(2-Fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared using2-((2-fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide.

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile wasprepared using 4-chloro-2-((3-cyanophenyl)amino)benzamide. ¹H NMR (400MHz, DMSO-d₆) δ 11.92 (s, 1H), 8.13-8.00 (m, 3H), 7.85 (dd, J=8.3, 1.7Hz, 2H), 7.34 (dt, J=8.5, 1.7 Hz, 1H), 6.43 (d, J=1.7 Hz, 1H).

Reference 3 Synthesis of7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzoic Acid

To a stirred solution of aniline (2 equiv) in THF (1 M) was added LDA (3equiv) at −78° C. and the reaction mixture was stirred for 10 min.4-chloro-2,6-difluorobenzoic acid (1 equiv) in THF (1 M) was added at−78° C. and the reaction mixture was stirred for 48 h at roomtemperature. After completion of the reaction, the crude was poured into1 N HCl solution and extracted with EtOAc. The combined organic layerswere separated, dried over anhydrous sodium sulfate, and concentratedunder reduced pressure to afford desired4-chloro-2-fluoro-6-(phenylamino)benzoic acid as a pale yellow solid.

Step 2: Synthesis of 4-chloro-2-fluoro-6-(phenylamino)benzamide

To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzoic acid(1 equiv) in DMF (0.4 M) were added HATU (1.5 equiv), DIPEA (5 equiv) atroom temperature and stirred for 30 min. Ammonium chloride (5 equiv) wasadded to the reaction mixture and stirring was continued for 16 h atroom temperature. After completion, the crude was poured into ice coldwater and stirred for 30 min, the solid filtered and dried under vacuumto afford 4-chloro-2-fluoro-6-(phenylamino)benzamide as an off-whitesolid.

Step 3: Synthesis of7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

To a stirred solution of 4-chloro-2-fluoro-6-(phenylamino)benzamide (1equiv) in DMF (0.33 M) was added NaH (2.2 equiv) at 0° C. and thereaction was stirred for 30 min. CDI (1.1 equiv) was added to thereaction mixture at 0° C. and stirring was continued for 30 min at 0° C.The crude was poured into ice cold water and the mixture was stirred for30 min, the solid filtered and dried under vacuum to afford the titlecompound (1.1 g, 57%) as an off white solid. ¹H NMR (400 MHz, DMSO-d₆) δ11.77 (br s, 1H), 7.61 (m, 3H), 7.44 (m, 2H), 7.29 (dd, J=10.8, 1.8 Hz,1H), 6.10 (s, 1H). m/z [M+H]⁺ 291.3

Proceeding as described in Reference 3, Step 2 above, the followingcompounds were prepared:

2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinamide was prepared using2-chloro-4-methoxy-6-(trifluoromethyl)nicotinic acid.

2,6-Dichloro-4-(trifluoromethyl)benzamide was prepared using2,6-dichloro-4-(trifluoromethyl) benzoic acid.

5-Bromo-2-fluoro-4-(trifluoromethyl)benzamide was prepared using5-bromo-2-fluoro-4-(trifluoromethyl)benzoic acid.

Reference 4 Synthesis of7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione

Step 1: Synthesis of4-chloro-2-((3-(methoxymethyl)phenyl)amino)benzamide

A vial was charged under air with 2-amino-4-chlorobenzamide (1.0 equiv),copper chloride (0.15 equiv), 3˜(methoxymethyl)phenylboronic acid (1.5equiv) and triethylamine (0.5 equiv). To the reaction vessel was addedMeOH (0.4 M) and the reaction mixture was stirred at room temperaturefor 3-12 h. The crude reaction mixture was directly purified by reversephase chromatography (20-65% MeCN/water) to give the title compound. m/z[M+H]⁺ 291.1

Step 2: Synthesis of7-chloro-1-[3-(methoxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dione

A vial was charged under nitrogen with4-chloro-2-((3-(methoxymethyl)phenyl)-amino)benzamide (1.0 equiv) andDMF (0.2 M). To the reaction mixture at 0° C. was added NaH (60% inmineral oil, 3.0 equiv) and the reaction mixture was stirred at roomtemperature for 10 min. CDI (1.5 equiv) was added and the reactionmixture was stirred at room temperature for 20 min. The reaction mixturewas quenched by the addition of MeOH and AcOH. The crude reactionmixture was directly purified by reverse phase column chromatography(20-75% MeCN/water, 0.1% formic acid) to give the title compound. ¹H NMR(400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 8.03 (dd, J=8.4, 1.3 Hz, 1H), 7.60(t, J=7.6 Hz, 1H), 7.50 (d, J=7.8 Hz, 1H), 7.41-7.34 (m, 2H), 7.30 (dt,J=8.4, 1.7 Hz, 1H), 6.30 (t, J=1.6 Hz, 1H), 4.50 (s, 2H) m/z [M+H]⁺317.1

Proceeding analogously as described above, the following compounds wereprepared:

7-Chloro-1-(3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting 3-hydroxyphenylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-[3-(2-hydroxyethyl)phenyl]-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting (3-(2-hydroxyethyl)phenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(3-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting (3-fluorophenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(3-methylphenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting m-tolylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-[3-(3-hydroxypropyl)phenyl]-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting 3-(3-hydroxypropyl)phenylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(3-chlorophenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting (3-chlorophenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-[3-(hydroxymethyl)phenyl]-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting (3-(hydroxymethyl)phenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile wasprepared by substituting (3-cyanophenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

tert-butyl(3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamatewas prepared by substituting3-((tert-butoxycarbonylamino)methyl)phenylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(3-methoxyphenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting (3-methoxyphenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(5-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting 3-fluoro-5-hydroxyphenylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(4-fluorophenyl)-1,3-dihydroquinazoline-2,4-dione wasprepared by substituting (4-fluorophenyl)boronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(2-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting 2-fluoro-3-hydroxyphenylboronic acid for3-(methoxymethyl)phenylboronic acid

7-Chloro-1-(4-fluoro-3-hydroxyphenyl)-1,3-dihydroquinazoline-2,4-dionewas prepared by substituting 4-fluoro-3-hydroxyphenylboronic acid for3-(methoxymethyl)phenylboronic acid

Reference 5 Synthesis of1-[3-(aminomethyl)phenyl]-7-chloro-1,3-dihydroquinazoline-2,4-dione

A vial was charged under nitrogen with tert-butyl(3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzyl)carbamate(1.0 equiv) and MeCN (0.2 M), 4N HCl/dioxane (10 equiv) was added andthe reaction mixture was stirred at room temperature for 30 min. Thesolvent was evaporated and the crude reaction mixture was directlypurified by reverse phase purification (10-45% MeCN/water, 0.1% formicacid) to give the title compound. ¹H NMR (400 MHz, DMSO-d6) δ 8.30 (s,1H), 8.05 (d, J=8.4 Hz, 1H), 7.60 (d, J=7.3 Hz, 2H), 7.44 (s, 1H),7.39-7.23 (m, 2H), 6.35 (s, 1H), 3.93 (s, 3H). m/z [M+H]⁺ 302.0

Reference 6 Synthesis of7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide

A slurry of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was treateddropwise with oxalyl chloride (1.35 equiv.) at room temperature. Thereaction mixture was then warmed to 55° C. for 1 h and was then furtherwarmed to reflux for 20 h. The reaction mixture was concentrated invacuo to afford the crude as a yellow oil. A solution of this crudeisocyanate in DCE (1.2 M) at 0° C. was added dropwise to a cooledsolution of o-toluidine in DCE (0.4 M). The ice bath was removed and thereaction mixture stirred at room temperature for 45 min. The solids werefiltered, washed with DCM, and dried to obtain the title compound as awhite solid. m/z [M+H]⁺ 324.0

Step 2: Synthesis of 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

A slurry of 2,4-dichloro-N-(o-tolylcarbamoyl)benzamide in DME:toluene(0.06 M, 1:1 v/v) was cooled to 0° C. and treated portion-wise with NaH(60% dispersion in oil, 3.1 equiv). After addition, the ice-bath wasremoved and the reaction mixture was warmed to reflux for 18 h. Thereaction mixture was cooled to RT and poured into 20% aq. HCl. Theresulting mixture was stirred vigorously and the off-white solid wasfiltered, washed with Et₂O and dried to obtain crude product which wasused in the next step without purification. m/z [M+H]⁺ 287.0

Proceeding analogously as described in Step 1 above, the followingcompounds were prepared:

4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamidewas prepared by substituting imidazo[1,2-a]pyridin-5-amine foro-toluidine and 4-(1, 1-difluoroethyl)-2-fluorobenzamide for2,4-dichlorobenzamide.

5-Cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide wasprepared using 5-cyano-4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide.

N-((2-Chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamidewas prepared by substituting 2-chloroaniline for o-toluidine and using4-(1,1-difluoroethyl)-2-fluorobenzamide for 2,4-dichlorobenzamide(Pharmablock, PBU1050).

4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide wasprepared by substituting imidazo[1,2-a]pyridin-5-amine for o-toluidineand 4-chloro-2-fluorobenzamide for 2,4-dichlorobenzamide.

4-Chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide wasprepared by substituting imidazo[1,2-a]pyridin-7-amine for o-toluidineand 4-chloro-2-fluorobenzamide for 2,4-dichlorobenzamide.

N-((2-Chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide wassynthesized using 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine.

2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide for 2,4-dichlorobenzamide and pyrimidin-2-amine.

4-Cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide wassynthesized using 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 3-methylpyrazin-2-amine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide wassynthesized using 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and pyrazin-2-amine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamidewas synthesized using 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-5-amine for o-toluidine

N-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide wasprepared by substituting 3-chloropyridin-2-amine for o-toluidine and4-ethyl-2-fluorobenzamide for 2,4-dichlorobenzamide.

N-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamidewas prepared by substituting 3-chloropyridin-2-amine for o-toluidine and4-(1,1-difluoroethyl)-2-fluorobenzamide for 2,4-dichlorobenzamide.

4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamidewas prepared by substituting imidazo[1,2-a]pyridin-7-amine foro-toluidine and 4-(1, 1-difluoroethyl)-2-fluorobenzamide for2,4-dichlorobenzamide.

2-Fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide wasprepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for2,4-dichlorobenzamide and pyrazin-2-amine for o-toluidine

2-Fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide wasprepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for2,4-dichlorobenzamide and pyridazin-3-amine for o-toluidine

2-Fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamidewas prepared by substituting 2-fluoro-4-(trifluoromethoxy)benzamide for2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-5-amine for o-toluidine.

2-Chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamidewas prepared by substituting 2-chloro-4-cyclopropylbenzamide for2,4-dichlorobenzamide and 3-(trifluoromethyl)pyrazin-2-amine foro-toluidine

5-Bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide wasprepared by substituting 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamidefor 2,4-dichlorobenzamide.

5-Bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide wasprepared by substituting 5-bromo-2-fluoro-4-(trifluoromethoxy)benzamidefor 2,4-dichlorobenzamide and aniline for o-toluidine

4-Bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide was preparedby substituting 4-bromo-2,5-difluorobenzamide for 2,4-dichlorobenzamideand 2-chloroaniline for o-toluidine

2,6-difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamidewas prepared by substituting 2,6-difluoro-4-(trifluoromethyl)benzamidefor 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine foro-toluidine.

4-cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamidewas prepared by substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and imidazo[1,2-a]pyridin-7-amine for o-toluidine

2-Chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamidewas prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamidefor 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine

2-Chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamidewas prepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamidefor 2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine foro-toluidine.

5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)carbamoyl)benzamide was prepared by substituting5-bromo-4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide and2-(trifluoromethyl)aniline for o-toluidine.

5-Bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamidewas prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-cyclopropylaniline for o-toluidine.

5-Bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide wasprepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-bromoaniline for o-toluidine

5-Bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamidewas prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-(trifluoromethyl)pyridin-3-amine foro-toluidine.

5-Bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamidewas prepared by substituting5-bromo-2-fluoro-4-(trifluoromethyl)benzamide for 2,4-dichlorobenzamideand 2-chloroaniline for o-toluidine

5-Bromo-N-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamidewas prepared by substituting 5-bromo-4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

N-((2-Chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamidewas prepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamidefor 2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

N-((2-Chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide wasprepared by substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-chloropyridin-3-amine for o-toluidine.

2-Fluoro-4-(trifluoromethyl)-N-((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamidewas prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for2,4-dichlorobenzamide and1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-aminefor o-toluidine.

2-Fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide was preparedby substituting 2-fluoro-4-(trifluoromethyl)benzamide for2,4-dichlorobenzamide and aniline for o-toluidine.

N-((3-Chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide wasprepared by substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 3-chloropyridin-2-amine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide was preparedby substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and pyrimidin-5-amine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide was prepared bysubstituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamide.

2-Fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamidewas prepared by substituting 2-fluoro-4-(trifluoromethyl)benzamide for2,4-dichlorobenzamide and (1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-4-yl) methanamine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-(((1-((2-(trimethylsilyl) ethoxy)methyl)-1H-imidazol-5-yl) methyl) carbamoyl) benzamide was prepared bysubstituting 4-cyclopropyl-2-fluorobenzamide for 2,4-dichlorobenzamideand (1-((2-(trimethylsilyl) ethoxy) methyl)-1H-imidazol-4-yl)methanaminefor o-toluidine.

N-((2-Bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide wasprepared by substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-bromoaniline for o-toluidine.

4-Cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide wasprepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for2,4-dichlorobenzamide and pyridin-3-amine for o-toluidine.

4-Cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide wasprepared by substituting 4-cyclopropyl-2-fluoro-6-methoxybenzamide for2,4-dichlorobenzamide.

4-chloro-N-((2-chlorophenyl)carbamoyl)-2,6-difluorobenzamide wasprepared by substituting 4-chloro-2,6-difluorobenzamide for2,4-dichlorobenzamide and 2-chloroaniline for o-toluidine.

4-Chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide was prepared bysubstituting 4-chloro-2,6-difluorobenzamide for 2,4-dichlorobenzamide.

N-(Benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide wasprepared by substituting 2-chloro-6-(trifluoromethyl)nicotinamide for2,4-dichlorobenzamide and benzylamine for o-toluidine.

4-Cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide wasprepared by substituting 4-cyclopropyl-2-fluorobenzamide for2,4-dichlorobenzamide and 2-methylpyridin-3-amine for o-toluidine.

2-Chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide was prepared by substituting2-chloro-6-(trifluoromethyl)nicotinamide for 2,4-dichlorobenzamide and2-chloro-6-fluoroaniline for o-toluidine.

Proceeding analogously as described in Step 2 above the followingcompounds were prepared:

7-Chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione was prepared bysubstituting 2-fluoroaniline for o-toluidine.

1-(3-Bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione was prepared bysubstituting 3-bromoaniline for o-toluidine.

7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-8-yl)quinazoline-2,4(1H,3H)-dionewas prepared using4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide.

7-cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrilewas prepared using5-cyano-4-cyclopropyl-2-fluoro-N-(o-tolylcarbamoyl)benzamide.

7-Chloro-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione wasprepared using4-chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide.

7-Chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione wasprepared using4-chloro-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide.

1-(2-Chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione wasprepared usingN-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

Reference 7 Synthesis of6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-cyclopropyl-2-fluorobenzamide

A vial was charged with 4-bromo-2-fluorobenzamide (1 equiv),cyclopropylboronic acid (3 equiv) and1,1′-bis(diphenylphosphino)ferrocene dichloropalladium (II) (0.1 equiv).A 1:1 mixture of toluene:t-butanol (0.1 M) was added followed by aqueouspotassium carbonate (2 M, 4 equiv). The reaction mixture was heated to100° C. for 2 h and then cooled. The crude reaction mixture was dilutedwith ethyl acetate, filtered and concentrated under reduced pressure.The residue was purified by flash column chromatography (0-100% ethylacetate/hexane) to give the title compound.

Step 2: Synthesis of 5-bromo-4-cyclopropyl-2-fluorobenzamide

A vial was charged with 4-cyclopropyl-2-fluorobenzamide (1 equiv) andN-bromo-succinimide (1.2 equiv). Trifluoroacetic acid (0.5 M) as addedfollowed by a catalytic amount of sulfuric acid. The reaction mixturewas heated to 40° C. for 2 h and then cooled. The crude reaction mixturewas poured into water and the title compound was collected byfiltration.

Step 3: Synthesis of5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide

A slurry of 5-bromo-4-cyclopropyl-2-fluorobenzamide (1 equiv.) in DCE(0.5 M) was treated dropwise with oxalyl chloride (1.35 equiv.) at roomtemperature. The reaction mixture was then warmed to 55° C. for for 1 hand was then further warmed to reflux for 20 h. The reaction mixture wasconcentrated in vacuo to afford the crude as a yellow oil. A solution ofthis crude isocyanate in DCE (1.2 M) at 0° C. was added dropwise to acooled solution of 2-chloroaniline in DCE (0.4 M). The ice bath wasremoved and the reaction mixture stirred at room temperature for 45 min.The solids were filtered, washed with DCM, and dried to obtain the titlecompound as a white solid.

Step 4: Synthesis of6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

A slurry of5-bromo-N-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide inDME:toluene (0.06 M, 1:1 v/v) was cooled to 0° C. and treatedportion-wise with NaH (60% dispersion in oil, 3.1 equiv). Afteraddition, the ice-bath was removed and the reaction mixture was warmedto reflux for 18 h. The reaction mixture was cooled to RT and pouredinto 20% aq. HCl. The resulting mixture was stirred vigorously and theoff-white solid was filtered, washed with Et₂O, dried to obtain crudeproduct which was used in the next step without purification. m/z [M+H]⁺392.0.

Reference 8 Synthesis of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide

A slurry of 2,4-dichlorobenzamide (1 equiv.) in DCE (0.5 M) was treateddropwise with oxalyl chloride (1.35 equiv.) at room temperature. Thereaction mixture was then warmed to 55° C. for 1 h and was then furtherwarmed to reflux for 20 h. The reaction mixture was concentrated invacuo to afford the crude 2,4-dichlorobenzoylisocyanate as a yellow oil.A solution of this crude product in DCE (1.2 M) at 0° C. was addeddropwise to a cooled solution of pyrazin-2-amine in DCE (0.4 M). The icebath was removed and the reaction mixture stirred at room temperaturefor 45 min. The solids were then filtered, washed with DCM, and dried toobtain the title compound as a white solid. m/z [M+H]⁺ 311.0.

Proceeding analogously as described above, the following compounds wereprepared.

2,4-Dichloro-N-(pyridin-2-ylcarbamoyl)benzamide

2,4-Dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide and pyridin-2-amine.

2,4-Dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide and pyridazin-3-amine.

2,4-Dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide and pyrimidin-5-amine.

N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using2,4-dichlorobenzamide and 1H-pyrazol-4-amine.

N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using2,4-dichlorobenzamide and 1H-imidazol-2-amine.

2,4-Dichloro-N-(thiazol-2-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide and thiazol-2-amine.

2,4-Dichloro-N-(thiazol-5-ylcarbamoyl)benzamide was prepared using2,4-dichlorobenzamide and thiazol-5-amine.

N-((1H-Pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide was prepared using2,4-dichlorobenzamide and 1H-pyrazol-5-amine.

2-Chloro-N-((2-chlorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamidewas prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and2-chloroaniline.

2-Chloro-N-((3-methylpyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamidewas prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and3-methylpyridin-2-amine.

2-Chloro-N-((3-chloropyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamidewas prepared using 2-chloro-6-(trifluoromethyl)nicotinamide and3-chloropyridin-2-amine.

2-Chloro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide was prepared using2-chloro-6-isopropylnicotinamidenicotinamide and aniline.

2,6-Difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide wasprepared using 2,6-difluoro-4-(trifluoromethyl)benzamide and aniline.

2-Fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamidewas prepared using 2-fluoro-4-(trifluoromethyl)benzamide and2-methylpyridin-3-amine.

N-((2-Chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide wasprepared using 2-fluoro-4-(trifluoromethoxy)benzamide and2-methylpyridin-3-amine.

4-Bromo-5-chloro-N-((2-chlorophenyl)carbamoyl)-2-fluorobenzamide wasprepared using 4-bromo-5-chloro-2-fluorobenzamide and 2-chloroaniline.

4-Cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamidewas prepared using 4-cyclopropyl-2-fluorobenzamide and2-(trifluoromethyl)pyridin-3-amine.

4-Cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamidewas prepared using 4-cyclopropyl-2-fluorobenzamide and2-(trifluoromethoxy)pyridin-3-amine.

Reference 9 Synthesis of7-chloro-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione

A slurry of 2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide in DMF (0.06M) at rt was treated dropwise with KHMDS (3 equiv). The reaction mixturewas heated to 95° C. for 18 h. Water was added to the reaction mixtureupon completion to fully solubilize the product, which was immediatelypurified via reverse phase column chromatography (20-60% MeCN/water,0.1% formic acid) to give the title compound. m/z [M+H]⁺ 276.0

Proceeding analogously as described above, the following compounds wereprepared by substituting2,4-dichloro-N-(pyrazin-2-ylcarbamoyl)benzamide:

7-Chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(pyridin-2-ylcarbamoyl)benzamide

7-Chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(pyrimidin-2-ylcarbamoyl)benzamide

7-Chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(pyridazin-3-ylcarbamoyl)benzamide

7-Chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(pyrimidin-5-ylcarbamoyl)benzamide

7-Chloro-1-(1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing N-((1H-pyrazol-4-yl)carbamoyl)-2,4-dichlorobenzamide

7-Chloro-1-(1H-imidazol-2-yl)quinazoline-2,4(1H,3H)-dione was preparedby using N-((1H-imidazol-2-yl)carbamoyl)-2,4-dichlorobenzamide

7-Chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(thiazol-2-ylcarbamoyl)benzamide

7-Chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2,4-dichloro-N-(thiazol-5-ylcarbamoyl)benzamide

7-Chloro-1-(1H-pyrazol-5-yl)quinazoline-2,4(1H,3H)-dione was prepared byusing N-((1H-pyrazol-5-yl)carbamoyl)-2,4-dichlorobenzamide

1-(2-Chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by usingN-((2-chlorophenyl)carbamoyl)-2-fluoro-6-(trifluoromethyl)nicotinamide

1-(3-Chloropyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by usingN-((2-chlorophenyl)carbamoyl)-2-fluoro-6-(trifluoromethyl)nicotinamide

1-(3-Methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneby using2-fluoro-N-((3-methylpyridin-2-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide

7-Isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione by using2-fluoro-6-isopropyl-N-(phenylcarbamoyl)nicotinamide

5-Fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione wasprepared by using2,6-difluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide

1-(2-Methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas prepared by using2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)-4-(trifluoromethyl)benzamide

1-(2-Chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione wasprepared by usingN-((2-chlorophenyl)carbamoyl)-2-fluoro-4-(trifluoromethoxy)benzamide

7-Bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione wasprepared by using4-bromo-5-chloro-N-((2-chlorophenyl)carbamoyl)-2-fluorobenzamide

7-Cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide

7-Cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using4-cyclopropyl-N-((2-(difluoromethoxy)pyridin-3-yl)carbamoyl)-2-fluorobenzamide

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione wasprepared by usingN-((2-chlorophenyl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide

7-Chloro-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using2,6-dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide.

7-Chloro-1-(2-chlorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using2,6-dichloro-N-((2-chlorophenyl)carbamoyl)nicotinamide.

7-Chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using 2,6-dichloro-N-(o-tolylcarbamoyl)nicotinamide

7-Chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was preparedby using 2,6-dichloro-N-(phenylcarbamoyl)nicotinamide.

7-Chloro-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using 2,6-dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide.

6-Bromo-1-phenyl-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione wasprepared by using5-bromo-2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethoxy)benzamide.

6-Bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione wasprepared by using5-bromo-2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethoxy)benzamide.

7-Cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using2-chloro-4-cyclopropyl-N-((3-(trifluoromethyl)pyrazin-2-yl)carbamoyl)benzamide.

1-(Imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dionewas prepared by using2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)-4-(trifluoromethoxy)benzamide.

1-(Pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione wasprepared by using2-fluoro-N-(pyridazin-3-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

1-(Pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione wasprepared by using2-fluoro-N-(pyrazin-2-ylcarbamoyl)-4-(trifluoromethyl)benzamide.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using4-cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide.

5-Fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using2,6-difluoro-4-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using4-cyclopropyl-2-fluoro-N-(imidazo[1,2-a]pyridin-5-ylcarbamoyl)benzamide.

7-Cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione was preparedby using 4-cyclopropyl-2-fluoro-N-(pyrazin-2-ylcarbamoyl)benzamide.

7-Cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione wasprepared by using4-cyclopropyl-2-fluoro-N-((3-methylpyrazin-2-yl)carbamoyl)benzamide.

1-(3-Chloropyridin-2-yl)-7-ethylquinazoline-2,4(1H,3H)-dione wasprepared by usingN-((3-chloropyridin-2-yl)carbamoyl)-4-ethyl-2-fluorobenzamide

1-(3-Chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dionewas prepared by usingN-((3-chloropyridin-2-yl)carbamoyl)-4-(1,1-difluoroethyl)-2-fluorobenzamide.

7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using4-(1,1-difluoroethyl)-2-fluoro-N-(imidazo[1,2-a]pyridin-7-ylcarbamoyl)benzamide.

1-(2-Chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrilewas prepared usingN-((2-chlorophenyl)carbamoyl)-5-cyano-2-fluoro-4-(trifluoromethyl)benzamide.

7-Bromo-1-(2-chlorophenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione wasprepared by using4-bromo-N-((2-chlorophenyl)carbamoyl)-2,5-difluorobenzamide.

1-(2-Chloropyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by using2-chloro-N-((2-chloropyridin-3-yl)carbamoyl)-6-(trifluoromethyl)nicotinamide.

7-(Trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by using2-Chloro-6-(trifluoromethyl)-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)nicotinamide.

6-Bromo-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dionewas prepared by using5-bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)phenyl)-carbamoyl)benzamide.

6-Bromo-7-cyclopropyl-1-(2-cyclopropylphenyl)quinazoline-2,4(1H,3H)-dionewas prepared by using5-bromo-4-cyclopropyl-N-((2-cyclopropylphenyl)carbamoyl)-2-fluorobenzamide.

6-Bromo-1-(2-bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione wasprepared by using5-bromo-N-((2-bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

6-Bromo-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dionewas prepared by using5-bromo-4-cyclopropyl-2-fluoro-N-((2-(trifluoromethyl)pyridin-3-yl)carbamoyl)benzamide.

5-Chloro-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione wasprepared by using2,6-dichloro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dionewas prepared by usingN-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide.

1-(2-Chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione wasprepared by usingN-((2-chloropyridin-3-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide

7-(Trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazoline-2,4(1H,3H)-dionewas prepared by using2-fluoro-4-(trifluoromethyl)-N-((1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)carbamoyl)benzamide.

1-Phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione was prepared byusing 2-fluoro-N-(phenylcarbamoyl)-4-(trifluoromethyl)benzamide.

1-(3-Chloropyridin-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione wasprepared by usingN-((3-chloropyridin-2-yl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

7-Cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione wasprepared by with4-cyclopropyl-2-fluoro-N-(pyrimidin-5-ylcarbamoyl)benzamide.

7-(Trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazoline-2,4(1H,3H)-dionewas prepared by using2-fluoro-4-(trifluoromethyl)-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl)benzamide.

7-Cyclopropyl-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazoline-2,4(1H,3H)-dionewas prepared by using2-chloro-4-cyclopropyl-N-(((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-5-yl)methyl)carbamoyl) benzamide.

1-(2-Bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione was preparedby using N-((2-Bromophenyl)carbamoyl)-4-cyclopropyl-2-fluorobenzamide.

7-Cyclopropyl-5-methoxy-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione wasprepared by using4-cyclopropyl-2-fluoro-6-methoxy-N-(pyridin-3-ylcarbamoyl)benzamide.

7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione wasprepared by using4-cyclopropyl-2-fluoro-6-methoxy-N-(o-tolylcarbamoyl)benzamide.

7-Chloro-5-fluoro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione was preparedby using 4-chloro-2,6-difluoro-N-(o-tolylcarbamoyl)benzamide.

1-Benzyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by usingN-(benzylcarbamoyl)-2-chloro-6-(trifluoromethyl)nicotinamide.

7-Cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione wasprepared by using4-cyclopropyl-2-fluoro-N-((2-methylpyridin-3-yl)carbamoyl)benzamide.

1-(2-Chloro-6-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by using2-chloro-N-((2-chloro-6-fluorophenyl)carbamoyl)-6-(trifluoromethyl)nicotinamide.

5-methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared by using2-chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamide.

Reference 10 Synthesis of7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-chloro-2,5-difluorobenzamide

To a stirred solution of 4-chloro-2,5-difluorobenzoic acid (1 equiv) inTHF (0.9 M) were added DIPEA (5 equiv), HATU (1.2 equiv) and NH₃ (0.4 Min THF, 3 equiv) in a sealed flask at 0° C. The resulting reactionmixture was stirred at room temperature for 16 h, and the reactionprogress was monitored by TLC. The reaction mixture was stirred withcrushed ice for 2 h, then filtered and dried under high vacuum to afford4-chloro-2,5-difluorobenzamide as a white solid.

Step 2: Synthesis of 4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide

To a stirred solution of 4-chloro-2,5-difluorobenzamide (1 equiv) intoluene (0.5 M) was added phenyl isocynate (1 equiv) and the resultingreaction mixture was refluxed for 16 h. The reaction mixture was dilutedwith EtOAc then washed with water. The combined organic layers wereseparated, dried over anhydrous sodium sulfate, and then concentrated.The crude was purified by column chromatography (10% EtOAc/Hexanes) toafford the title compound as an off white solid.

Step 3: Synthesis of7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

To a stirred solution of4-chloro-2,5-difluoro-N-(phenylcarbamoyl)benzamide (1 equiv) in THF(0.25 M) was added KHMDS (1 M in THF, 1 equiv) at 0° C. The resultingreaction mixture was warmed to RT and 18-crown-6 (0.01, g, cat.) wasadded. After heating at 75° C. for 4 h, the reaction mixture was dilutedwith EtOAc and then washed with water. The organic layers were driedover sodium sulfate and concentrated. The crude solid was washed withdiethyl ether and n-pentane, then filtered and dried under high vacuumto afford the title compound as an off white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 12.13-11.95 (m, 1H), 7.96 (d, J=8.61 Hz, 1H), 7.77-7.55(m, 3H), 7.46 (m, 2H), 6.43 (d, J=5.89 Hz, 1H). m/z [M+H]⁺ 291.13.

Proceeding analogously as described in Reference 1 Step 2 above, thefollowing compounds were prepared:

2,6-Dichloro-N-((2-fluorophenyl)carbamoyl)nicotinamide was preparedusing 1-fluoro-2-isocyanatobenzene and 2,6-dichloronicotinamide

2,6-dichloro-n-((2-chlorophenyl)carbamoyl)nicotinamide was preparedusing 1-chloro-2-isocyanatobenzene and 2,6-dichloronicotinamide

2,6-dichloro-N-(o-tolylcarbamoyl)nicotinamide was prepared using1-isocyanato-2-methylbenzene and 2,6-dichloronicotinamide

2,6-Dichloro-N-(phenylcarbamoyl)nicotinamide was prepared using2,6-dichloronicotinamide

2,6-Dichloro-N-(pyridin-3-ylcarbamoyl)nicotinamide was prepared using3-isocyanatopyridine and 2,6-dichloronicotinamide

2,6-Dichloro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide wasprepared using 2,6-dichloro-4-(trifluoromethyl)benzamide and1-isocyanato-2-methylbenzene.

2-chloro-4-methoxy-N-(phenylcarbamoyl)-6-(trifluoromethyl)nicotinamidewas prepared using 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinamideand phenyl isocyanate.

Proceeding analogously as described in Reference 10, Step 3 above, thefollowing compounds were prepared:

7-Cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

6-Bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

6-Bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

Reference 11 Synthesis of7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 3,4-dichloro-2-(phenylamino)benzoic Acid

A flask was charged with 2-amino-3,4-dichlorobenzoic acid (1 equiv),triethylamine (4 equiv) and bromobenzene (1 equiv). Dioxane (1 M) andcopper (II) acetate (1 equiv) were added and the reaction mixture washeated to 110° C. for 18 h. The reaction mixture was cooled, additionalbromobenzene was added (1 equiv) and then heated to 110° C. for 24 h.The crude reaction mixture was diluted with saturated ammonium chloridesolution and extracted with dichloromethane. The organic layer waswashed with 1 N HCl and brine, dried over sodium sulfate, filtered andconcentrated under reduced pressure. The residue was purified by flashcolumn chromatography (0-50% ethyl acetate/hexane) to give the titlecompound.

Step 2: Synthesis of 3,4-dichloro-2-(phenylamino)benzamide

To a stirred solution of 3,4-dichloro-2-(phenylamino)benzoic acid (1equiv) in THF (0.9 M) were added DIPEA (5 equiv), HATU (1.2 equiv) andthen added NH₃ (0.4 M in THF, 3 equiv) in a sealed flask at 0° C. Theresulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was stirred with crushed ice for 2 h, then filtered anddried under high vacuum to afford the title compound as a white solid.

Step 3: Synthesis of 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione

A vial was charged under nitrogen with3,4-dichloro-2-(phenylamino)benzamide (1.0 equiv) and DMF (0.2 M). Tothe reaction vessel at 0° C. was added NaH (60% in mineral oil, 3.0equiv) and the reaction mixture was stirred at room temperature for 10min. CDI (1.5 equiv) was added and the reaction mixture was stirred atroom temperature for 20 min. The reaction was quenched by the additionof MeOH (0.5 mL) and AcOH (0.2 mL). The crude reaction mixture wasdirectly purified by reverse phase column chromatography (20-75%MeCN/water, 0.1% formic acid). ¹H NMR (400 MHz, Chloroform-d) δ 8.29 (s,1H), 8.13 (d, J=8.5 Hz, 1H), 7.48-7.43 (m, 3H), 7.29 (d, J=7.8 Hz, 2H).m/z [M+H]⁺ 307.0 Reference 12 Synthesis of7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-chloro-2-fluoro-3-methylbenzamide

A flask was charged with 4-chloro-2-fluoro-3-methylbenzoic acid, (1equiv), hydroxybenzotriazole (0.2 equiv) andN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.5equiv). DMF (0.5 M) was added followed by diisopropylethyl amine (2equiv). The reaction mixture was stirred for 15 min, followed byaddition of ammonium chloride (5 equiv). The reaction mixture wasstirred at room temperature for 2 h. The crude reaction mixture wasdiluted with saturated sodium bicarbonate solution and extracted withdichloromethane. The organic layer was washed with 1 N HCl and brine,dried over sodium sulfate, filtered and concentrated under reducedpressure to give the title compound.

Step 2: Synthesis of4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide

A slurry of 4-chloro-2-fluoro-3-methylbenzamide (1 equiv.) in DCE (0.5M) was treated dropwise with oxalyl chloride (1.35 equiv.) at roomtemperature. The reaction mixture was then warmed to 55° C. for 1 h andwas then further warmed to reflux for 20 h. The reaction mixture wasconcentrated in vacuo to afford the crude as a yellow oil. A solution ofthis crude 4-chloro-2-fluoro-3-methylbenzoyl isocyanate in DCE (1.2 M)at 0° C. was added dropwise to a cooled solution of aniline in DCE (0.4M). The ice bath was removed and the reaction mixture stirred at roomtemperature for 45 min. The solids were then filtered, washed with DCM,and dried to obtain the title compound as a white solid.

Step 3: Synthesis of7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dione

A slurry of 4-chloro-2-fluoro-3-methyl-N-(phenylcarbamoyl)benzamide inDMF (0.06 M) was cooled to 0° C. and treated portion-wise with NaH (60%dispersion in oil, 3.1 equiv). After addition was complete the ice-bathwas removed and the reaction mixture was refluxed for 18 h. The reactionmixture was cooled to rt and poured into 20% aq. HCl. The resultingmixture was stirred vigorously, and the off-white solid was filtered,washed with Et₂O, dried to obtain the title compound and used as such inthe next step without purification. ¹H NMR (400 MHz, Chloroform-d) δ8.21 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.47 (t, J=7.2 Hz, 2H), 7.42 (d,J=6.9 Hz, 1H), 7.37 (d, J=8.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 1.71 (s,3H). m/z [M+H]⁺ 287.0.

Proceeding analogously as described above, following compounds wereprepared by substituting for 4-chloro-2-fluoro-3-methylbenzamide:

2-Fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide was preparedby using o-toluidine and 2-fluoro-4-(trifluoromethyl)benzamide

1-(o-Tolyl)-7-trifluoromethylquinazoline-2,4(1H,3H)-dione was preparedby using 2-fluoro-N-(o-tolylcarbamoyl)-4-(trifluoromethyl)benzamide.

Reference 13 Synthesis of1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Step 1: Synthesis of 2-(phenylamino)-6-(trifluoromethyl)nicotinamide

A round bottom flask was purged with nitrogen and a solution of KHMDS(2.5 equiv, 1 M THF) was added to the flask containing a vigorouslystirred suspension of 2-chloro-6-(trifluoromethyl)nicotinamide (1 equiv)and aniline (1.1 equiv) in toluene or THF (0.4 M) at room temperature.After 2 h, the reaction mixture was evaporated to half volume to removeTHF. The solid portion was filtered, washed with additional toluene, anddried under vacuum to provide the title compound. m/z [M+H]⁺ 282.1

Step 2: Synthesis of1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Proceeding analogously as described in Reference 2 above butsubstituting 4-chloro-2-(pyridin-3-ylamino)benzamide with2-(phenylamino)-6-(trifluoromethyl)nicotinamide, gave the titlecompound.

Proceeding analogously as described in Reference 13, Step 1 above, thefollowing compounds were prepared:

2-((2-Fluorophenyl)amino)-6-(trifluoromethyl)nicotinamide was preparedby substituting aniline with 2-fluoroaniline.

2-((2-Bromophenyl)amino)-6-(trifluoromethyl)nicotinamide was prepared bysubstituting aniline with 2-bromoaniline.

Reference 14 Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile

A vial was charged with6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione (1equiv) and copper cyanide (2 equiv). Dimethylformamide was added (0.5 M)and the reaction mixture was heated to 120° C. for 18 h and then cooled.The crude reaction mixture was filtered and purified by reverse phasepurification (30-60% MeCN/water, 0.1% formic acid) to give the titlecompound. m/z [M+H]⁺ 338.0.

Proceeding analogously as described in Reference 14 above, the followingcompounds were prepared:

1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrilewas prepared using6-bromo-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrilewas prepared using6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

7-Cyclopropyl-2,4-dioxo-1-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrilewas prepared using6-bromo-7-cyclopropyl-1-(2-(trifluoromethyl)phenyl)quinazoline-2,4(1H,3H)-dione.

7-Cyclopropyl-1-(2-cyclopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrilewas prepared using6-bromo-7-cyclopropyl-1-(2-cyclopropylphenyl)quinazoline-2,4(1H,3H)-dione.

1-(2-Bromophenyl)-7-cyclopropyl-2, 4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile was prepared using6-bromo-1-(2-bromophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-hydroxy-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-hydroxyquinazolin-2(1H)-one.

Reference 15 Synthesis of7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione

To a stirred solution of1-(3-bromophenyl)-7-chloro-4-hydroxyquinazolin-2(1H)-one (8 g, 22.8mmol) in 1,4-dioxane (0.11 M) in a sealed tube was added potassiumfluoride (3 equiv) and tributyl(vinyl)stannane (1.5 equiv) at roomtemperature. The reaction mixture was degassed with argon gas for 20min. Pd (OAc)₂ (10 mol %) was added and the reaction mixture was againdegassed for 5 min. The resulting reaction mixture was stirred at 100°C. for 16 h. Upon completion, the reaction mixture was filtered througha celite bed. The filtrate was diluted with water and extracted withEtOAc. The combined organic layer was washed with water, brine solution,dried over Na₂SO₄. The organics were then filtered and concentratedunder reduced pressure to get crude compound. The crude was purified bycolumn chromatography (1:6 EtOAc/hex) to afford the title compound as ayellow solid. m/z [M−H]⁺ 298.73.

Reference 16 Synthesis of7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

Step 1: Synthesis of 2-bromo-4,6-dichlorobenzoic acid

Butyl nitrite (2 equiv) was added dropwise at 0° C. to a suspension ofCuBr₂ (1.2 equiv) in acetonitrile (0.25 M). The reaction was stirred for10 min and 2-amino-4,6-dichlorobenzoic acid (1 equiv) was added portionwise. The reaction mixture was stirred at 0° C. for 2 h, then allowed towarm to room temperature and stirred for 16 h. The reaction mixture wascooled to 0° C., and the reaction mixture was quenched with TN HCl. Thesolution was then extracted with diethyl ether. The pH of the organicphase was adjusted to pH 12 with 2 N NaOH. The water phase was adjustedto pH 2 with 2 N HCl and then extracted with diethyl ether. The combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated under reduced pressure to afford2-bromo-4,6-dichlorobenzoic acid as an off white solid.

Step 2: Synthesis of 2,4-dichloro-6-vinylbenzoic Acid

To a stirred solution of 2-bromo-4,6-dichlorobenzoic acid (1 equiv) inDMSO:H₂O (3:1, 0.2 M) was added vinyl boronic acid pinacol ester (1.2equiv), K₂CO₃ (3 equiv) and Pd(dppf)Cl₂ (5 mol %) at room temperature.The reaction mixture was purged under argon for 10 min., and then heatedto 120° C. and stirred for 16 h. The reaction mixture was diluted with 1N HCl and EtOAc and then washed with brine solution. The combinedorganic layers were separated, dried over anhydrous sodium sulfate, andthen concentrated under reduced pressure. The crude was purified usingcolumn chromatography (20% EtOAc/Hexane) then concentrated under reducedpressure to afford 2,4-dichloro-6-vinylbenzoic acid as an off whitesemi-solid.

Step 3: Synthesis of 2,4-dichloro-6-ethylbenzoic Acid

To a stirred solution of 2,4-dichloro-6-vinylbenzoic acid (1 equiv) inEtOAc (0.3 M) was added 10% Pd/C (10 mol %) at room temperature. Thereaction mixture was stirred under a hydrogen atmosphere (1 atm) for 16h and then filtered through a celite bed and washed several times withethyl acetate. The filtrate was concentrated under reduced pressure toafford 2,4-dichloro-6-ethylbenzoic acid as viscous liquid which wasfurther used in the next step without any purification.

Step 4: Synthesis of 2,4-dichloro-6-ethylbenzamide

To a stirred solution of 2,4-dichloro-6-ethylbenzoic acid (1 equiv) inDMF (0.4 M) was added HATU (1.5 equiv), DIPEA (5 equiv) followed byaddition of NH₄Cl (5 equiv) at room temperature. Then the reactionmixture was stirred at RT for 16 h and then diluted with EtOAc andwashed with water. The combined organic layers were separated, driedover anhydrous sodium sulfate, and then concentrated under reducedpressure to give a crude product. The crude product was purified usingcolumn chromatography (30% EtOAc/Hexane) and concentrated under reducedpressure to afford the title compound as an off white solid.

Step 5: Synthesis of 2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide

To a stirred solution of 2,4-dichloro-6-ethylbenzamide (1 equiv) in DCE(0.3 M) were added oxalyl chloride (1.9 equiv) at room temperature. Thereaction was stirred at 100° C. for 16 h and then concentrated to givecrude 2,4-dichloro-6-ethylbenzoylisocyanate as gummy liquid. To astirred solution of o-toluidine (1.2 equiv) in DCE (1.4 M) at 0° C. wasslowly added the crude isocyanate in suspension of DCE (1.5 M) at 0° C.The reaction mixture was stirred at room temperature for 2 h and thenconcentrated under vacuum. The solid residue was washed with pentane anddried under vacuum to afford the title compound as an off white solid.

Step 6: Synthesis of7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

To a stirred solution of2,4-dichloro-6-ethyl-N-(o-tolylcarbamoyl)benzamide (1 g, 2.9 mmol) inDMF (0.7 M) was slowly added KHMDS (2 equiv, 1.0 M in THF) dropwise at0° C. The reaction was stirred at 100° C. for 1 h and then diluted withwater and slowly added 1 N HCl. The precipated solids were filtered andwashed with water, dried under vacuum to afford the title compound as apale yellow solid.

Step 7: Synthesis of7-cyclopropyl-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one

To a stirred solution of7-chloro-5-ethyl-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one (1 equiv) intoluene:H₂O (8:2, 0.6 M) was added cyclopropyl boronic acid (10 equiv),K₃PO₄ (3 equiv) at room temperature. The reaction mixture was purgedwith argon for 5 min, and Pd(PPh₃)₄(10 mol %) was added. After stirringthe reaction mixture at 150° C. in the microwave for 1 h, it was dilutedwith water and extracted with EtOAc. The combined organic layers wereseparated, washed with brine solution, dried over anhydrous sodiumsulphate, filtered and concentrated. The crude was purified by columnchromatography (10-20% EtOAc/Hexane) and concentrated under reducedpressure to afford the title compound as an off white solid. m/z [M+H]⁺321.41.

Reference 17 Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-bromo-2-fluoro-6-hydroxybenzoic Acid

To a stirred solution of 4-bromo-2,6-difluorobenzoic acid (1 equiv) inN-methyl-2-pyrrolidone (0.85 M) was added sodium hydroxide (4 equiv) atRT. The reaction mixture was stirred for 45 min. at 120° C. and thencooled to RT and ice water was added. This mixture was acidified with 2N HCl (100 mL) until approximately pH 1 and the precipitates werefiltered and washed with water to afford the title compound as an offwhite solid.

Step 2: Synthesis of methyl 4-bromo-2-fluoro-6-hydroxybenzoate

To a stirred solution of 4-bromo-2-fluoro-6-hydroxybenzoic acid (1equiv) in methanol (0.4 M) was added thionyl chloride (0.36 equiv) at 0°C. The reaction mixture was stirred at 90° C. for 72 h and thenconcentrated under reduced pressure. The residue was quenched withsaturated aqueous sodium bicarbonate solution and extracted with DCM.The combined organic layer was washed with brine solution, dried overanhydrous Na₂SO₄, filtered, concentrated under reduced pressure toafford the title compound as an off white solid.

Step 3: Synthesis of methyl 4-bromo-2-(difluoromethoxy)-6-fluorobenzoate

To a stirred solution of methyl 4-bromo-2-fluoro-6-hydroxybenzoate (1equiv) in acetonitrile/water (1:1, 0.2 M) was added potassium hydroxide(20 equiv) at room temperature. The solution was cooled to −78° C. anddiethyl (bromodifluoromethyl)phosphonate (2 equiv) was added. Thereaction mixture was stirred for 20 min. at RT and then diluted withwater and extracted with ether. The combined organic layers were washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure to afford crude product. Purification by columnchromatography (5% EtOAC/Hexane) gave the title compound as a colorlessliquid.

Step 4: Synthesis of methyl4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate

To a stirred solution of methyl4-bromo-2-(difluoromethoxy)-6-fluorobenzoate (1 equiv) in toluene/water(1:1, 0.2 M) were added cyclopropylboronic acid (1.5 equiv) and Na₂CO₃(3 equiv). The resulting reaction mixture was degassed for 20 min underargon atmosphere and PdCl₂(dppf) DCM (10 mol %) was added. Afterstirring at 120° C. for 16 h, the reaction mixture was filtered throughcelite and the filtrate was extracted with EtOAc. The combined organiclayers were washed with brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford the crudeproduct. Purification by column chromatography using silica (5%EtOAc/Hexanes) and concentrated under reduced pressure gave the titlecompound as a colorless liquid.

Step 5: Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoicAcid

To a stirred solution of methyl4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoate (1 equiv) inMeOH/THF/H₂O (2:2:1, 0.17 M) was added LiOH.H₂O (2 equiv) at roomtemperature. The reaction mixture was stirred for 16 h at RT. Methanolwas removed under reduced pressure and water was added to the remainingresidue and the solution was acidified with 2 N HCl to about pH 1. Theprecipitates were filtered and dried to afford the title compound as anoff white solid.

Step 6: Synthesis of 4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

To a stirred solution of4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoic acid (1 equiv) in DMF(0.4 M) were added NH₄Cl (5 equiv), DIPEA (3 equiv) and HATU (1.5 equiv)at RT. The reaction mixture was stirred at RT for 16 h and then dilutedwith water and extracted with EtOAc. The combined organic layers werewashed with cold water and brine. The organic layer was dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford the title compound as a light yellow solid.

Step 7: Synthesis ofN-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide

To a stirred solution of4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzamide (1 equiv) in DCE(0.4 M) was added oxalyl chloride (1.4 equiv) and the reaction mixturewas stirred at 100° C. for 20 h. The reaction mixture was concentratedunder reduced pressure to afford crude4-cyclopropyl-2-(difluoromethoxy)-6-fluorobenzoyl isocyanate. A stirredsolution of 2-chloroaniline (1 equiv) in DCE (0.7 M) was added to amixture of the crude isocyanate in THF (1 M) at 0° C. and the reactionmixture was stirred at RT for 2 h. The reaction mixture was diluted withwater and extracted with EtOAc and the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄, filtered andconcentrated. The crude product was purified by column chromatography(10% EtOAc/Hexane) and concentrated under reduced pressure to afford thetitle compound as a light brown solid.

Step 8: Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

To a stirred solution ofN-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-(difluoro-methoxy)-6-fluorobenzamide(1 equiv) in DMF (0.5 M) was added KHMDS (2 equiv, 1 M in THF) dropwiseat 0° C. The reaction mixture was stirred at 100° C. for 2 h and thencooled to RT and acidified with 2 N HCl to approximately pH 1. The whiteprecipitates were filtered, washed with water, and dried to afford thetitle compound as a yellow solid. m/z [M+H]⁺ 379.3.

Reference 18 Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione

Step 1: Synthesis of 4-bromo-2-fluoro-6-methoxybenzamide

To a stirred solution of 4-bromo-2,6-difluorobenamide (1 equiv) in MeOH(200 ml) was added NaOMe (2.5 equiv) and the reaction mixture wasstirred at 70° C. for 16 h. The reaction mixture was concentrated underreduced pressure and the residue was diluted with water and extractedwith EtOAc. The combined organic layers were separated, washed withbrine, dried over anhydrous sodium sulfate. The solution was filteredand concentrated under reduced pressure to afford crude product. Thecrude was purified by column chromatography (40% EtOAc/Hexane) andconcentrated under reduced pressure to afford the title compound as awhite solid.

Step 2: Synthesis of 4-cyclopropyl-2-fluoro-6-methoxybenzamide

To a stirred solution of 4-bromo-2-fluoro-6-methoxybenzamide (1 equiv)in toluene/water (4:1, 0.3 M) were added cyclopropylboronic acid (1.5equiv), K₂CO₃ (3 equiv), tributylphosphine (20 mol %), Pd₂(dba)₃ (10 mol%) and the reaction mixture was stirred at 115° C. for 16 h. Thereaction mixture was diluted with water and extracted with EtOAc and thecombined organic layers were separated, washed with brine, and driedover anhydrous sodium sulfate. The solution was then filtered andconcentrated under reduced pressure to afford crude product which waspurified by column chromatography (30% EtOAc/Hexane) and concentratedunder reduced pressure to afford the title compound as an off whitesolid.

Step 3: Synthesis ofN-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxy-benzamide

To a stirred solution of 4-cyclopropyl-2-fluoro-6-methoxybenzamide (1equiv) in DCE (0.25 M) was added oxalyl chloride (1.3 equiv) at 0° C.and the reaction mixture was stirred at 55° C. for 1 h and then refluxedfor 20 h. The crude 4-cyclopropyl-2-fluoro-6-methoxybenzoyl isocyanatein DCE (1.4 M) was added to a solution of 2-chloroaniline (1 equiv) inDCE (0.7 M) at 0° C. under nitrogen atmosphere and stirred at RT for 2h. The solids were filtered and washed with diethyl ether and driedunder vacuum to afford the title compound as a brown solid.

Step 4: Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one

To a stirred solution ofN-((2-chlorophenyl)carbamoyl)-4-cyclopropyl-2-fluoro-6-methoxybenzamide(1 equiv) in DMF (0.05 M) was added KHMDS (1M in THF, 2.5 equiv)dropwise at 0° C. and the reaction mixture was stirred at 100° C. for 4h. The reaction mixture was diluted with water and acidified toapproximately pH 1 with 2 N HCl. The solids were filtered and driedunder vacuum to afford the title compound as an off white solid. m/z[M+H]⁺ 343.34.

Reference 19 Synthesis of(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-4yl)methanamine

A vial was charged under nitrogen with1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazole-4-carbonitrile (1.0equiv) and THF (0.5 M). LAH (2.0 equiv) was added and the reactionmixture was stirred at 70° C. for 2 h. The reaction mixture was cooledto 0° C. and quenched with wet Na₂SO₄. The reaction mixture was filteredon a pad of Celite by washing with EtOAc. The filtrate was dried overNa₂SO₄, filtered and concentrated to give the title compound; m/z [M+H]⁺228.28.

Reference 20 Synthesis of1-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine

Step 1:1-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one

A vial was charged under nitrogen with 1-(1H-imidazol-4-yl)ethan-1-one(1.0 equiv) and THF (0.5 M). Sodium hydride (2.0 equiv) was added at 0°C. and the reaction mixture was stirred at room temperature for 1 h.(2-(chloromethoxy)ethyl)trimethylsilane (1.6 equiv) was added at 0° C.and the mixture was stirred at room temperature for 2 h. The reactionmixture was quenched with ice-cold water and diluted with EtOAc. Theorganic layer was dried over Na₂SO₄, filtered and concentrated.Purification by silica gel chromatography (20-25% EtOAc/Hexane) affordedthe title product; m/z [M+H]⁺ 241.4.

Step 2: Synthesis of1-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-oneoxime

A vial was charged under nitrogen with1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-one (1equiv) and methanol (0.5 M). Hydroxylamine hydrochloride (1.2 equiv) andK₂CO₃ (3 equiv) were added and the mixture was stirred at roomtemperature for 2 h. The reaction mixture was passed through a pad ofCelite by washing with methanol. The filtrate was dried over Na₂SO₄,filtered and concentrated to give the title product; m z [M+H]⁺ 256.39.

Step 3:1-(1-((2-(Trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-amine

A vial was charged under nitrogen with1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethan-1-oneoxime (1 equiv) and EtOH. Zinc (15 equiv) and ammonium chloride (10equiv) were added at room temperature and the reaction mixture wasstirred at 80° C. for 48 h. The reaction mixture was filtered through apad of Celite by washing with ethanol. The filtrate was dried overNa₂SO₄, filtered and concentrated. Purification by reverse phasechromatography (30% ACN/water) afforded the title compound; m/z [M+H]⁺242.38.

Reference 21 Synthesis of 5-cyano-4-cyclopropyl-2-fluorobenzamide

A vial was charged with 5-bromo-4-cyclopropyl-2-fluorobenzamide (1equiv) and copper cyanide (2 equiv). Dimethylformamide was added (0.5 M)and the reaction mixture was heated to 120° C. for 18 h and then cooled.The crude reaction mixture was filtered and purified by reverse phasepurification (30-60% MeCN/water, 0.1% formic acid) to give the titlecompound. m/z [M+H]⁺ 205.0.

Reference 22 Synthesis of2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinic Acid

Step 1: ethyl 2-chloro-4-methoxy-6-(trifluoromethyl)nicotinate

To a vial charged under nitrogen with ethyl2,4-dichloro-6-(trifluoromethyl)nicotinate (1.0 equiv) in DMF (0.9 M)was added MeOH (1.0 equiv) at room temperature. Then the reactionmixture was cooled to 0° C. and slowly added portion wise NaH (60%) (1.0equiv). The reaction mixture was stirred at same temperature for 1 h,then quenched with cold water and extracted with EtOAc. The combinedorganic layers were separated and washed with brine solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford the title compound; m/z [M+H]⁺ 284.23.

Step 2: 2-Chloro-4-methoxy-6-(trifluoromethyl)nicotinic Acid

To a stirred solution of ethyl2-chloro-4-methoxy-6-(trifluoromethyl)nicotinate (1.0 equiv) inMeOH:THF:H₂O (2:7:1, 0.5 M) was added LiOH (5.0 equiv) at roomtemperature. The reaction mixture was heated at 80° C. and stirred for16 h. The reaction mixture was diluted with water and adjusted to pH 4with 1 N HCl, extracted with EtOAc. The combined organic layers wereseparated and washed with brine solution, dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure to afford the titlecompound; m/z [M+H]⁺ 256.11.

Reference 23 Synthesis of6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione

To a solution of1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione (1equiv.) in trifluoroacetic acid (0.3 M) was added N-bromosuccinimide(1.2 equiv.) and sulfuric acid (18 M, 0.1 equiv.). The reaction mixturewas heated to 40° C. for 4 h and then cooled. The crude mixture waspoured into water and the precipitate formed was collected by filtrationand dried under vacuum to afford the title compound as a white solid.m/z [M+H]⁺ 415.0/416.9.

Proceeding analogously as described above,6-bromo-1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dionewas prepared using1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

Reference 24 Synthesis of7-ethyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A vial was charged with7-chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (1 equiv),potassium ethyltrifluoroborate (3 equiv), potassium tert-butoxide (3equiv) andchloro(crotyl)(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)palladium(II)(0.1 equiv). A 9:1 mixture of toluene:water (0.1 M) was added. Thereaction mixture was heated to 100° C. for 2 h and then cooled. Thecrude reaction mixture was diluted with ethyl acetate, filtered andconcentrated under reduced pressure. The residue was purified bypreparatory HPLC (40-65% MeCN/water, 0.1% formic acid) to give the titlecompound. m/z [M+H]⁺ 374.05

Proceeding analogously as described in Reference 24 above, the followingcompounds were prepared by substituting for7-chloro-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

7-Ethyl-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione was preparedby using 7-chloro-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

1-(2-Chlorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using7-chloro-1-(2-chlorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

7-Ethyl-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using7-chloro-1-(2-fluorophenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

7-Ethyl-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione wasprepared by using7-chloro-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

Reference 25 Synthesis of1-(2-Chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dione

A vial was purged with nitrogen and then charged with6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione(1.0 equiv), vinyl boronic acid pinacol ester (4 equiv) and K₂CO₃ (5equiv). To the reaction vessel was added toluene:H₂O (4:1, 0.4 M)followed by addition of Pd(dppf)Cl₂ DCM complex (0.1 equiv). Thereaction mixture was heated at 100° C. for 16 h. The reaction mixturewas then diluted with water and extracted with EtOAc. The combinedorganic layers were separated, washed with brine solution, dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure toafford crude product. The crude reaction mixture was directly purifiedby column chromatography using silica gel (10-20% EtOAC/Hexane). Thefractions were combined to provide the title compound as a yellow solid.m/z [M+H]⁺ 367.12

Proceeding analogously as described in Reference 25 above, the followingcompounds were prepared by substituting for6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand vinyl boronic acid pinacol ester:

1-(2-Chlorophenyl)-7-cyclopropyl-6-vinylquinazoline-2,4(1H,3H)-dione wasprepared by using6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

6-Chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dionewas prepared by using7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione andcyclopropylboronic acid.

1-(2-Chlorophenyl)-6-methyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dionewas prepared by using6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand methylboronic acid.

1-(2-Chlorophenyl)-7-cyclopropyl-6-methylquinazoline-2,4(1H,3H)-dionewas prepared by using6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione andmethylboronic acid.

Reference 26 Synthesis of1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde

A vial was charged under nitrogen with1-(2-chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dione(1.0 equiv) in THF:H₂O (10:3, 0.5 M) was added OsO₄ (0.1 M in H₂O) (2.0equiv) followed by addition of NaIO₄ (4.0 equiv) and the reactionmixture was stirred at room temperature for 1 h. The reaction mixturewas filtered under celite bed, the filtrate was diluted with water andextracted with EtOAc. The combined organic layers were separated, washedwith brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to give the title compound. m/z[M+H]⁺ 369.04.

Proceeding analogously as described in Reference 26 above,1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbaldehydewas prepared by substituting1-(2-chlorophenyl)-7-(trifluoromethyl)-6-vinylquinazoline-2,4(1H,3H)-dionewith1-(2-chlorophenyl)-7-cyclopropyl-6-vinylquinazoline-2,4(1H,3H)-dione.

Reference 27 Synthesis of1-(2-Chlorophenyl)-6-(difluoromethyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

A vial was charged under nitrogen with1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde(1.0 equiv) in DCM (0.7 M) was added DAST (10 equiv) at 0° C. followedby addition of ethanol (catalytic) and heated at 60° C. for 16 h. Thereaction mixture was quenched with saturated NaHCO₃ solution andextracted with EtOAc. The combined organic layers were separated, washedwith brine solution, dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure to afford crude product. The crudewas purified by column chromatography (10-20% EtOAC/Hexane). The purefractions were collected and concentrated under reduced pressure to givethe title compound. m/z [M+H]⁺ 391.11.

Proceeding analogously as described in Reference 27 above,1-(2-chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)quinazoline-2,4(1H,3H)-dionewas prepared by substituting1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbaldehydewith1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbaldehyde.

Reference 28 Synthesis of5-methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

A 20 mL vial under nitrogen was added5-fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione (1.0equiv), MeOH (0.6 M) and MeONa (5.4 N in MeOH, 10 equiv). The reactionmixture was stirred for 60 minutes at room temperature. The reactionvessel was acidified by adding AcOH. The crude solution was purified byreverse phase chromatography (20-60% MeCN/water, with 0.10% Formicacid). m/z [M+H]⁺ 337.0

Example 1 Synthesis of 4,7-dichloro-1-phenylquinazolin-2(1H)-one

To a stirred solution of 7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one(1 equiv) in ACN (0.1 M) were added DIPEA (5 equiv) and POCl₃ (2 equiv)at 0° C. The reaction was stirred at 100° C. for 4 h, then poured in icewater and extracted with EtOAc. The combined organics were washed withNaHCO₃ solution, dried with sodium sulfate, filtered and concentratedunder reduced pressure below 10° C. to afford the title compound as abrown solid.

Example 2 Synthesis of7-chloro-4-(methylamino)-1-phenylquinazolin-2(1H)-one

To a stirred solution of 4,7-dichloro-1-phenylquinazolin-2(1H)-one (0.3g, 1.03 mmol) in DMF (10 ml) were added TEA (2 equiv) and methylamine (5equiv) and the reaction mixture was stirred at 70° C. for 2 h. The crudecompound was purified by column chromatography (50-90% EtOAc/Hexanes).The pure fractions were concentrated to afford 7 the title compound asan off-white solid. ¹H NMR (400 MHz, DMSO-d6): δ=8.64-8.53 (m, 1H), 8.10(d, J=8.8 Hz, 1H), 7.62-7.56 (m, 2H), 7.54-7.48 (m, 1H), 7.33-7.22 (m,3H), 6.32-6.27 (m, 1H), 2.98 (d, J=4.2 Hz, 3H). m/z [M+H]⁺ 286.23.

Proceeding analogously as described above, the following compounds wereprepared by substituting for7-chloro-4-hydroxy-1-phenylquinazolin-2(1H)-one and methylamine asneeded:

7-Bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one by using7-bromo-1-phenylquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, CD₃OH) δ 7.90 (d, J=8.7 Hz, 1H), 7.65 (t, J=7.5 Hz,2H), 7.58 (t, J=7.4 Hz, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.32 (d, J=7.6 Hz,2H), 6.68 (s, 1H), 3.13 (s, 3H). m z [M+H]⁺ 330.0

7-Fluoro-4-(methylamino)-1-phenylquinazolin-2(1H)-one was prepared byusing 7-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, CD₃OH) δ 8.06 (dd, J=8.7, 5.9 Hz, 1H), 7.64 (t, J=7.5Hz, 2H), 7.58 (d, J=7.2 Hz, 1H), 7.32 (d, J=7.7 Hz, 2H), 7.02 (t, J=8.4Hz, 1H), 6.21 (d, J=10.7 Hz, 1H), 3.13 (s, 3H). m/z [M+H]⁺ 270.0

7-chloro-1-(3-fluoro-5-hydroxyphenyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) (10.42 (s, 1H), 8.64 (d, J=4.1 Hz, 1H), 8.10(d, J=8.6 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 6.73 (d, J=10.7 Hz, 1H), 6.65(d, J=9.1 Hz, 1H), 6.52 (s, 1H), 6.44 (s, 1H), 2.96 (s, 4H). m/z [M+H]⁺320.0

7-Chloro-6-fluoro-4-(methylamino)-1-phenylquinazolin-2(1H)-one wasprepared by using 7-chloro-6-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ ppm 8.62-8.57 (m, 1H), 8.21 (d, J=9.9 Hz,1H), 7.62-7.57 (m, 2H), 7.56-7.50 (m, 1H), 7.36-7.30 (m, 2H), 6.40 (d,J=6.0 Hz, 1H), 3.33 (s, 3H). m/z [M+H]⁺ 304.08

7-Chloro-5-fluoro-4-(methylamino)-1-phenylquinazolin-2(1H)-one wasprepared by using 7-chloro-5-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione

¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.08-7.96 (m, 1H), 7.64-7.49 (m, 3H),7.35-7.24 (m, 3H), 6.11 (s, 1H), 3.03-2.93 (m, 3H). m/z [M+H]⁺ 304.1

7-Chloro-4-(methylamino)-1-(pyridin-4-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(pyridin-4-yl)quinazoline-2,4(1H,3H)-dione.

7-Chloro-4-(methylamino)-1-(pyridin-3-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(pyridin-3-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(pyridin-2-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(pyridin-2-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(pyrimidin-2-yl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(pyrimidin-2-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(pyridazin-3-yl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(pyridazin-3-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(pyrimidin-5-yl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(1H-pyrazol-4-yl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(1H-pyrazol-4-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-1-(1H-imidazol-2-yl)-4-(methylamino)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(1H-imidazol-2-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(thiazol-2-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(thiazol-2-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(thiazol-5-yl)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(thiazol-5-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(methylamino)-1-(1H-pyrazol-5-yl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(1H-pyrazol-5-yl)quinazoline-2,4(1H,3H)-dione

7-Chloro-4-(cyclopropylamino)-1-phenylquinazolin-2(1H)-one was preparedby using cyclopropyl amine

¹H NMR (400 MHz, DMSO-d₆): δ=8.46 (d, J=3.9 Hz, 1H), 8.17 (d, J=8.8 Hz,1H), 7.63-7.57 (m, 2H), 7.55-7.49 (m, 1H), 7.33-7.30 (m, 2H), 7.28-7.25(m, 1H), 6.29 (d, J=2.0 Hz, 1H), 3.11-3.04 (m, 1H), 0.84-0.77 (m, 2H),0.73-0.67 (m, 2H). m/z [M+H]⁺ 312.20.

7-Chloro-4-(oxetan-3-ylamino)-1-phenylquinazolin-2(1H)-one was preparedby using oxetan-3-amine.

¹H NMR (400 MHz, DMSO-d₆) δ=9.02 (d, J=5.0 Hz, 1H), 8.30 (d, J=8.8 Hz,1H), 7.63-7.57 (m, 2H), 7.55-7.49 (m, 1H), 7.35-7.26 (m, 3H), 6.30 (d,J=1.8 Hz, 1H), 5.18-5.08 (m, 1H), 4.88-4.84 (m, 2H), 4.70-4.65 (m, 2H).m/z [M+H]⁺ 328.19.

7-Chloro-1-phenyl-4-((tetrahydrofuran-3-yl)amino)quinazolin-2(1H)-onewas prepared by using tetrahydrofuran-3-amine

¹H NMR (400 MHz, DMSO-d₆): δ=8.44 (d, J=6.1 Hz, 1H), 8.33 (d, J=8.6 Hz,1H), 7.57-7.63 (m, 2H), 7.54-7.50 (m, 1H), 7.33-7.27 (m, 3H), 6.29 (d,J=1.8 Hz, 1H), 4.71-4.79 (m, 1H), 3.96-3.90 (m, 2H), 3.79-3.70 (m, 2H),2.30-2.21 (m, 1H), 2.06 (td, J=12.2, 6.2 Hz, 1H). m/z [M+H]⁺ 342.12

4-(Benzylamino)-7-chloro-1-phenylquinazolin-2(1H)-one prepared by usingbenzylamine

¹H NMR (400 MHz, DMSO-d₆): δ=9.13 (t, J=5.7 Hz, 1H), 8.25 (d, J=8.6 Hz,1H), 7.63-7.57 (m, 2H), 7.54-7.47 (m, 1H), 7.27-7.42 (m, 8H), 6.31 (d,J=1.8 Hz, 1H), 4.76 (d, J=5.7 Hz, 2H). m/z [M+H]⁺ 362.12

7-Chloro-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one was prepared byusing dimethylamine

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 7.76 (d, J=8.8 Hz, 1H), 7.55-7.59 (m,2H), 7.47-7.51 (m, 1H), 7.26-7.29 (m, 2H), 7.06 (dd, J=8.7, 2.1 Hz, 1H),6.56 (d, J=2.0 Hz, 1H), 3.38 (s, 6H). m/z [M+H]⁺ 300.21

4-(Azetidin-1-yl)-7-chloro-1-phenylquinazolin-2(1H)-one was prepared byusing azetidine

¹H NMR (400 MHz, DMSO-d₆): δ=7.82 (d, J=8.8 Hz, 1H), 7.62-7.57 (m, 2H),7.54-7.49 (m, 1H), 7.28 (d, J=7.2 Hz, 2H), 7.19 (dd, J=8.7, 2.1 Hz, 1H),6.30 (d, J=2.0 Hz, 1H), 4.53-4.02 (m, 4H), 2.45-2.41 (m, 2H). m/z [M+H]⁺312.20

7-Chloro-4-(3-hydroxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-one wasprepared by using pyrrolidin-3-ol

¹H NMR (400 MHz, DMSO-d₆): δ=8.16 (d, J=8.8 Hz, 1H), 7.62.7.58 (m, 2H),7.49-7.54 (m, 1H), 7.32-7.29 (m, 2H), 7.20 (dd, J=8.8, 2.1 Hz, 1H), 6.32(d, J=2.1 Hz, 1H), 5.12 (d, J=3.1 Hz, 1H), 4.41 (br s, 1H), 3.84-4.02(m, 3H), 3.69-3.64 (m, 1H), 1.92-2.08 (m, 2H). m/z [M+H]⁺ 342.12

7-Chloro-4-(4-methylpiperazin-1-yl)-1-phenylquinazolin-2(1H)-one wasprepared by using 1-methylpiperazine

¹H NMR (400 MHz, CDCl₃): δ=8.25 (d, J=1.8 Hz, 1H), 7.57-7.65 (m, 3H),7.54-7.50 (m, 1H), 7.30-7.27 (m, 2H), 7.10 (dd, J=8.6, 2.0 Hz, 1H), 6.60(d, J=2.0 Hz, 1H), 4.08-3.85 (m, 8H), 2.84-2.79 (m, 4H), 2.48 (s, 3H).m/z [M+H]⁺ 355.18

7-Chloro-4-morpholino-1-phenylquinazolin-2(1H)-one was prepared by usingmorpholine.

¹H NMR (400 MHz, CDCl₃): δ=7.64-7.57 (m, 3H), 7.53-749 (m, 1H), 7.29 (d,J=7.2 Hz, 2H), 7.08 (dd, J=8.7, 1.9 Hz, 1H), 6.59 (d, J=1.8 Hz, 1H),3.88 (s, 8H). m/z [M+H]⁺ 342.12

7-Chloro-1-phenyl-4-(1H-pyrazol-1-yl)quinazolin-2(1H)-one was preparedby using pyrazole

¹H NMR (400 MHz, CDCl₃); δ=9.49 (d, J=9.0 Hz, 1H), 8.87 (d, J=2.6 Hz,1H), 7.94 (d, J=0.9 Hz, 1H), 7.67-7.62 (m, 2H), 7.61-7.55 (m, 1H),7.36-7.32 (m, 2H), 7.25 (d, J=2.0 Hz, 1H), 6.69 (d, J=2.0 Hz, 1H),6.58-6.56 (m, 1H). m/z [M+H]⁺ 323.13

7-Chloro-4-(ethylamino)-1-phenylquinazolin-2(1H)-one was prepared byusing ethylamine

¹H NMR (400 MHz, DMSO-d₆): δ=8.57 (t, J=5.3 Hz, 1H), 8.17 (d, J=8.8 Hz,1H), 7.62-7.57 (m, 2H), 7.55-7.48 (m, 1H), 7.33-7.26 (m, 3H), 6.29 (d,J=2.0 Hz, 1H), 3.57-3.49 (m, 2H), 1.25-1.21 (m, 3H). m/z [M+H]⁺ 300.21

7-Chloro-4-((2,2-difluoroethyl)amino)-1-phenylquinazolin-2(1H)-one wasprepared by using 2,2-difluoroethan-1-amine

¹H NMR (400 MHz, DMSO-d₆): δ=8.90 (br s, 1H), 8.21 (d, J=8.8 Hz, 1H),7.63-7.58 (m, 2H), 7.55-7.50 (m, 1H), 7.34-7.29 (m, 3H), 6.42-6.25 (m,2H), 3.98-3.89 (m, 2H). m/z [M+H]⁺ 336.13

7-Chloro-1-phenyl-4-(pyridin-2-ylamino)quinazolin-2(1H)-one by usingpyridin-2-amine

¹H NMR (400 MHz, DMSO-d₆): δ=13.84 (br s, 1H), 8.51 (br d, J=3.3 Hz,1H), 8.42 (d, J=8.3 Hz, 1H), 7.94-7.89 (m, 1H), 7.66-7.48 (m, 5H),7.39-7.33 (m, 2H), 7.22 (dd, J=5.5, 6.8 Hz, 1H), 6.31 (br s, 1H). m/z[M+H]⁺ 349.12

7-Chloro-1-phenyl-4-(pyridin-4-ylamino)quinazolin-2(1H)-one by usingpyridin-4-amine

¹H NMR (400 MHz, DMSO-d₆): δ=10.16 (d, J=9.4 Hz, 1H), 8.54-8.44 (m, 3H),7.97 (dd, J=3.5, 16.9 Hz, 2H), 7.65-7.60 (m, 2H), 7.58-7.52 (m, 1H),7.42-7.35 (m, 3H), 6.37 (br s, 1H). m/z [M+H]⁺ 349.12

7-Bromo-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one was prepared byusing 7-bromo-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine

¹H NMR (400 MHz, Chloroform-d) δ 7.68 (d, J=8.7 Hz, 1H), 7.57 (t, J=7.6Hz, 2H), 7.49 (t, J=7.3 Hz, 1H), 7.28 (s, 2H), 7.21 (d, J=8.7 Hz, 1H),6.72 (s, 1H), 3.38 (s, 6H). m z [M+H]⁺ 344.0

4-(Dimethylamino)-7-fluoro-1-phenylquinazolin-2(1H)-one was prepared byusing 7-fluoro-1-phenylquinazoline-2,4(1H,3H)-dione and dimethylamine

¹H NMR (400 MHz, Chloroform-d) δ 7.89-7.82 (m, 1H), 7.55 (t, J=7.4 Hz,2H), 7.47 (t, J=7.3 Hz, 1H), 7.28 (s, 2H), 6.81 (t, J=8.3 Hz, 1H), 6.23(d, J=10.6 Hz, 1H), 3.39 (s, 6H). m/z [M+H]⁺ 284.1

7-chloro-4-(dimethylamino)-1-(4-fluorophenyl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(4-fluorophenyl)quinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=8.7 Hz, 1H), 7.41 (dt, J=17.4,8.5 Hz, 4H), 7.21 (d, J=8.7 Hz, 1H), 6.38 (s, 1H), 3.31 (s, 8H). m/z[M+H]⁺ 318.0.

4-(Dimethylamino)-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydroquinazolin-2-onewas prepared by using7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 10.40 (s, 1H), 8.04 (d, J=8.8 Hz, 1H), 7.22(d, J=8.8 Hz, 1H), 6.73 (d, J=10.9 Hz, 1H), 6.66 (d, J=8.9 Hz, 1H), 6.53(s, 1H), 6.48 (s, 1H), 3.30 (s, 6H). m/z [M+H]⁺ 334.0

4-(azetidin-1-yl)-7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazolin-2(1H)-onewas prepared by using7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione andazetidine

¹H NMR (400 MHz, DMSO-d₆) (7.82 (d, J=8.6 Hz, 1H), 7.21 (d, J=8.6 Hz,1H), 6.73 (d, J=10.7 Hz, 1H), 6.63 (d, J=9.3 Hz, 1H), 6.50 (s, 1H), 6.45(s, 1H), 4.96-4.53 (m, 3H), 4.53-4.12 (m, 3H), 3.83 (s, 1H), 2.46-2.39(m, 2H). m/z [M+H]⁺ 346.0

7-chloro-4-(cyclopropyl(methyl)amino)-1-(3-fluorophenyl)quinazolin-2(1H)-onewas prepared by using7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione andN-methylcyclopropanamine

¹H NMR (400 MHz, DMSO-d₆) (8.44 (d, J=8.8 Hz, 1H), 7.64 (q, J=7.7 Hz,1H), 7.39 (t, J=8.4 Hz, 1H), 7.30 (d, J=9.7 Hz, 1H), 7.20 (d, J=7.9 Hz,2H), 6.37 (s, 1H), 3.52 (s, 1H), 3.22 (s, 3H), 0.91 (d, J=6.3 Hz, 2H),0.68 (s, 2H). m/z [M+H]⁺ 344.0

4-Amino-7-chloro-1-(5-fluoro-3-hydroxyphenyl)hydroquinazolin-2-one wasprepared by using7-chloro-1-(3-fluoro-5-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione andammonia (7 M in MeOH).

¹H NMR (400 MHz, DMSO-d₆) (8.17 (s, 1H), 8.14 (d, J=8.7 Hz, 1H), 8.07(s, 1H), 7.27 (d, J=8.5 Hz, 1H), 6.73 (d, J=10.9 Hz, 1H), 6.66 (d, J=9.2Hz, 1H), 6.52 (s, 1H), 6.44 (s, 1H). m/z [M+H]⁺ 306.0

4-Amino-7-chloro-1-(4-fluorophenyl)hydroquinazolin-2-one was prepared byusing 7-chloro-1-(4-fluorophenyl)quinazoline-2,4(1H,3H)-dione andammonia (7 M in MeOH).

¹H NMR (400 MHz, DMSO-d₆) (8.16 (t, J=8.5 Hz, 2H), 8.08 (s, 1H), 7.40(p, J=8.2, 7.7 Hz, 4H), 7.27 (d, J=8.4 Hz, 1H), 6.35 (s, 1H). m/z [M+H]⁺290.0

7,8-Dichloro-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one was preparedby using 7,8-dichloro-1-phenylquinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, Chloroform-d) δ 7.57 (dd, J=35.1, 8.6 Hz, 1H),7.47-7.41 (m, 1H), 7.41-7.36 (m, 2H), 7.32 (q, J=8.9, 7.5 Hz, 3H), 3.36(s, 6H). m/z [M+H]⁺ 334.0

7-Chloro-4-(dimethylamino)-8-methyl-1-phenylquinazolin-2(1H)-one wasprepared by using 7-chloro-8-methyl-1-phenylquinazoline-2,4(1H,3H)-dioneand dimethylamine

¹H NMR (400 MHz, Chloroform-d) δ 7.55 (d, J=8.7 Hz, 1H), 7.44-7.37 (m,2H), 7.33 (dd, J=15.5, 7.8 Hz, 3H), 7.20 (d, J=8.8 Hz, 1H), 3.35 (s,6H), 1.71 (s, 3H). m/z [M+H]⁺ 314.0

7-Chloro-4-(dimethylamino)-1-(o-tolyl)quinazolin-2(1H)-one was preparedby using 7-chloro-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (brs, 1H), 8.15 (d, J=12 Hz 1H), 7.44(m, 3H), 7.31 (d, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 6.21 (s, 1H), 3.01(s, 3H).

7-Chloro-4-(dimethylamino)-1-(2-fluorophenyl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(2-fluorophenyl)quinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (brs, 1H), 8.15 (d, J=8 Hz 1H),7.63-7.40 (m, 4H), 7.34 (d, J=8 Hz, 1H), 6.38 (s, 1H), 2.99 (s, 3H).

3-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)benzonitrile wasprepared by using3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)benzonitrile anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.06 (d, J=8.7 Hz, 1H), 8.00 (d, J=7.6 Hz,1H), 7.93 (s, 1H), 7.80 (t, J=7.8 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 7.24(d, J=8.7 Hz, 1H), 6.40 (s, 1H), 3.32 (s, 6H). m/z [M+H]⁺ 325.1

4-(Dimethylamino)-7-chloro-1-(3-methoxyphenyl)hydroquinazolin-2-one wasprepared by using7-chloro-1-(3-methoxyphenyl)quinazoline-2,4(1H,3H)-dione anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=8.7 Hz, 1H), 7.51 (t, J=8.1 Hz,1H), 7.21 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.90 (s, 1H), 6.87(d, J=7.7 Hz, 1H), 6.39 (s, 1H), 3.79 (s, 3H), 3.30 (s, 8H). m/z [M+H]⁺330.0

7-Chloro-1-(3-methoxyphenyl)-4-(methylamino)hydroquinazolin-2-one wasprepared by using7-chloro-1-(3-methoxyphenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (s, 1H), 8.11 (d, J=8.7 Hz, 1H), 7.50(t, J=8.0 Hz, 1H), 7.28 (d, J=8.3 Hz, 1H), 7.09 (d, J=8.4 Hz, 1H), 6.90(s, 4H), 6.36 (s, 1H), 3.79 (s, 3H), 2.98 (d, J=4.4 Hz, 3H). m/z [M+H]⁺316.1

7-Chloro-1-(3-fluorophenyl)-4-(methylamino)hydroquinazolin-2-one wasprepared by using7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (d, J=4.8 Hz, 1H), 8.13 (d, J=8.6 Hz,1H), 7.64 (q, J=7.7 Hz, 1H), 7.39 (t, J=8.7 Hz, 1H), 7.30 (d, J=8.9 Hz,2H), 7.19 (d, J=7.9 Hz, 1H), 6.36 (d, J=2.0 Hz, 1H), 2.98 (d, J=4.2 Hz,3H). m/z [M+H]⁺ 304.1

7-Chloro-4-(methylamino)-1-(3-methylphenyl)hydroquinazolin-2-one wasprepared by substituting7-chloro-1-(m-tolyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=5.0 Hz, 1H), 8.11 (d, J=8.6 Hz,1H), 7.48 (t, J=7.7 Hz, 1H), 7.34 (d, J=7.7 Hz, 1H), 7.31-7.24 (m, 1H),7.11 (s, 1H), 7.08 (d, J=7.8 Hz, 1H), 6.32 (d, J=1.9 Hz, 1H), 2.98 (d,J=4.3 Hz, 3H). m/z [M+H]⁺ 300.1

7-Chloro-1-(3-chlorophenyl)-4-(methylamino)hydroquinazolin-2-one wasprepared by using7-chloro-1-(3-chlorophenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=4.9 Hz, 1H), 8.16-8.07 (m, 1H),7.66-7.57 (m, 2H), 7.51 (t, J=1.8 Hz, 1H), 7.31 (tt, J=8.7, 1.8 Hz, 2H),6.35 (t, J=1.7 Hz, 1H), 2.98 (dd, J=4.3, 1.7 Hz, 3H). m/z [M+H]⁺ 320.0

1-[7-Chloro-1-(3-fluorophenyl)-2-oxohydroquinazolin-4-yl]azetidine-3-carbonitrilewas prepared by using7-chloro-1-(3-fluorophenyl)quinazoline-2,4(1H,3H)-dione andazetidine-3-carbonitrile

¹H NMR (400 MHz, MeCN-d₃) δ 7.70 (d, J=8.7 Hz, 1H), 7.63 (q, J=7.7 Hz,1H), 7.32 (t, J=8.7 Hz, 1H), 7.19 (d, J=8.7 Hz, 1H), 7.14 (t, J=7.6 Hz,2H), 6.57 (s, 1H), 4.77 (d, J=34.8 Hz, 4H), 3.91-3.79 (m, 1H). m/z[M+H]⁺ 355.10

1-(3-Bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one wasprepared by using 1-(3-bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=8.7 Hz, 1H), 7.73 (d, J=8.1 Hz,1H), 7.61 (s, 1H), 7.56 (t, J=8.0 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.22(d, J=8.8 Hz, 1H), 6.37 (s, 1H), 3.31 (s, 6H). m/z [M+H]⁺ 378.0

7-Chloro-4-((2-(dimethylamino)ethyl)amino)-1-phenylquinazolin-2(1H)-onewas prepared by using N¹,N¹-dimethylethane-1,2-diamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (br s, 1H), 8.23-8.08 (m, 2H),7.62-7.40 (m, 3H), 7.29-7.18 (m, 3H), 6.26 (d, J=1.8 Hz, 1H), 3.57 (brs, 2H), 2.56 (br t, J=6.6 Hz, 2H), 2.23 (s, 6H). m/z [M+H]⁺ 343.1

7-Chloro-4-((2-(dimethylamino)ethyl)(methyl)amino)-1-phenylquinazolin-2(1H)-onewith was prepared by using N¹,N¹,N²-trimethylethane-1,2-diamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.23 (br s, 1H), 8.06 (d, J=8.8 Hz, 1H),7.61-7.50 (m, 3H), 7.31 (d, J=7.2 Hz, 2H), 7.20 (dd, J=2.0, 8.8 Hz, 1H),6.33 (d, J=2.0 Hz, 1H), 3.80 (br t, J=6.5 Hz, 2H), 3.35 (s, 3H), 2.64(t, J=6.5 Hz, 2H), 2.21 (s, 6H). m/z [M+H]⁺ 357.1

7-Methyl-4-(methylamino)-1-phenylpyrido[4,3-d]pyrimidin-2(1H)-one wasprepared by using7-methyl-1-phenylpyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.82-8.75 (m, 1H), 7.60-7.55(m, 2H), 7.54-7.50 (m, 1H), 7.28 (d, J=7.2 Hz, 2H), 6.13 (s, 1H), 2.99(d, J=4.5 Hz, 3H), 2.35-2.32 (m, 3H). m/z [M+H]⁺ 267.3

7-Methyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one wasprepared by using7-methyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.59-8.56 (m, 1H), 8.34 (d, J=8.1 Hz, 1H),7.49-7.44 (m, 2H), 7.40-7.35 (m, 1H), 7.21-7.17 (m, 2H), 7.11 (d, J=8.1Hz, 1H), 2.98 (d, J=4.5 Hz, 3H), 2.29 (s, 3H). m/z [M+H]⁺ 267.3

7-Chloro-1-phenyl-4-(pyrrolidin-1-yl)quinazolin-2(1H)-one was preparedby using pyrrolidine

¹H NMR (400 MHz, Chloroform-d) δ 7.92 (d, J=8.8 Hz, 1H), 7.59-7.54 (m,2H), 7.50-7.46 (m, 1H), 7.29-7.27 (m, 2H), 7.05 (dd, J=2.0, 8.8 Hz, 1H),6.54 (d, J=2.0 Hz, 1H), 3.97 (br t, J=6.7 Hz, 4H), 2.07-2.02 (m, 4H).m/z [M+H]⁺ 326.2

7-Chloro-1-phenyl-4-(piperidin-1-yl)quinazolin-2(1H)-one was prepared byusing piperidine

¹H NMR (400 MHz, Chloroform-d) δ 7.64-7.54 (m, 3H), 7.52-7.46 (m, 1H),7.31-7.27 (m, 2H), 7.06 (dd, J=2.0, 8.7 Hz, 1H), 6.55 (d, J=2.0 Hz, 1H),3.79 (br s, 4H), 1.79 (br s, 6H). m/z [M+H]⁺ 340.2

4-Amino-7-chloro-1-phenylquinazolin-2(1H)-one was prepared by usingammonia (7 M in MeOH)

¹H NMR (400 MHz, DMSO-d₆) δ 8.17-8.02 (m, 3H), 7.60-7.47 (m, 3H),7.33-7.18 (m, 3H), 6.29 (d, J=1.8 Hz, 1H). m/z [M+H]⁺ 272.1

7-Chloro-4-methoxy-1-phenylquinazolin-2(1H)-one was prepared by usingmethanol

¹H NMR (400 MHz, Chloroform-d): δ 7.94 (d, J=8.6 Hz, 1H), 7.63-7.57 (m,2H), 7.56-7.50 (m, 1H), 7.31-7.27 (m, 2H), 7.18-7.14 (m, 1H), 6.58 (d,J=1.8 Hz, 1H), 4.21 (s, 3H). m z [M+H]⁺ 287.2

7-Chloro-4-(3-hydroxyazetidin-1-yl)-1-phenylquinazolin-2(1H)-one wasprepared by using azetidin-3-ol

¹H NMR (400 MHz, DMSO-d₆) δ 7.84 (d, J=8.8 Hz, 1H), 7.62-7.57 (m, 2H),7.54-7.49 (m, 1H), 7.28 (d, J=7.3 Hz, 2H), 7.19 (dd, J=2.0, 8.7 Hz, 1H),6.30 (d, J=2.0 Hz, 1H), 5.91 (d, J=6.0 Hz, 1H), 5.01-3.69 (m, 5H). m/z[M+H]⁺ 328.1

(R)-7-Chloro-4-(3-fluoropyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-onewas prepared by using (R)-3-fluoropyrrolidine

¹H NMR (400 MHz, Chloroform-d) δ 8.14 (s, 1H), 7.93 (d, J=8.8 Hz, 1H),7.59 (t, J=7.6 Hz, 2H), 7.51 (t, J=7.3 Hz, 1H), 7.28 (s, 1H), 7.12 (d,J=8.8 Hz, 1H), 6.59 (s, 1H), 5.39 (d, J=52.3 Hz, 1H), 4.31-4.19 (m, 2H),4.19-4.09 (m, 2H), 2.48 (td, J=14.4, 5.4 Hz, 1H), 2.26-2.04 (m, 1H). m/z[M+H]⁺ 344.0

7-Chloro-1-(3-fluorophenyl)-4-((3-hydroxypropyl)(methyl)amino)quinazolin-2(1H)-onewas prepared by using 3-(methylamino)propan-1-ol

¹H NMR (400 MHz, DMSO-d₆) (8.04 (d, J=8.8 Hz, 1H), 7.64 (q, J=7.7 Hz,1H), 7.39 (t, J=8.0 Hz, 1H), 7.31 (d, J=9.6 Hz, 1H), 7.21 (t, J=8.5 Hz,2H), 6.39 (s, 1H), 3.79-3.72 (m, 2H), 3.33 (s, 4H), 1.98-1.87 (m, 2H).m/z [M+H]⁺ 362.0

7-Chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=5.0 Hz, 1H), 8.16 (d, J=8.6 Hz,1H), 7.84-7.68 (m, 1H), 7.65-7.44 (m, 3H), 7.33 (d, J=8.6 Hz, 1H), 6.22(d, J=2.3 Hz, 1H), 3.00 (d, J=4.3 Hz, 3H). m/z [M+H]⁺ 322.00

1-(2-Bromophenyl)-7-chloro-4-(methylamino)quinazolin-2(1H)-one wasprepared by using 7-chloro-1-(2-bromophenyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=5.0 Hz, 1H), 8.09 (d, J=8.6 Hz,1H), 7.82 (d, J=8.1 Hz, 1H), 7.62-7.36 (m, 3H), 7.25 (d, J=8.5 Hz, 1H),6.12 (t, J=1.7 Hz, 1H), 2.99-2.82 (m, 3H). m/z [M+H]⁺ 366.00

(R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)-1-phenylquinazolin-2(1H)-onewas prepared by using (R)-3-hydroxypyrrolidine

¹H NMR (400 MHz, DMSO-d₆) δ=8.16 (d, J=8.4 Hz, 1H), 7.61-7.58 (m, 2H),7.54-7.53 (m, 1H), 7.52-7.51 (m, 2H), 7.19 (dd, J=2.0, 8.8 Hz, 1H), 6.31(d, J=2.0 Hz, 1H), 5.11 (br s, 2H), 4.41 (s, 1H), 4.01-3.85 (m, 3H),3.66 (d, J=12 Hz, 1H), 2.03-1.96 (m, 2H). m/z [M+H]⁺ 342.19.

1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (br s, 1H), 8.80 (d, J=8.1 Hz, 1H),7.81 (dd, J=8.1, 1.8 Hz, 1H), 7.71-7.58 (m, 1H), 7.47 (m, 3H), 3.04 (s,3H).

4-(Methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

4-((2,2-Difluoroethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using 2,2-difluoroethan-1-amine

¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (s, 1H), 8.46 (d, J=8.6 Hz, 1H), 7.64(d, J=8.6 Hz, 1H), 7.57-7.34 (m, 3H), 7.27 (d, J=7.7 Hz, 1H), 6.60-6.07(m, 2H), 3.97 (q, J=16.3 Hz, 2H), 1.96 (d, J=2.0 Hz, 3H). m/z [M+H]⁺384.00

7-Cyclopropyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-one wasprepared by using 7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ=8.4 (d, J=3.6 Hz, 1H), 7.96 (d, J=6.8 Hz,1H), 7.45-7.36 (m, 3H), 7.14 (d, J=6.8 Hz, 1H), 6.80 (dd, J=1.2, 6.8 Hz,1H), 5.99 (d, J=1.2 Hz, 1H), 2.96 (d, J=3.6 Hz, 3H), 1.93 (d, J=8.0 Hz,3H), 0.91 (dd, J=1.2, 6.4 Hz, 2H), 0.95-0.93 (m, 2H); LCMS: m/z [M+H]⁺306.33.

6-Bromo-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.64 (s, 1H), 7.60 (t, J=7.4Hz, 2H), 7.55-7.50 (m, 1H), 7.33 (d, J=7.5 Hz, 2H), 6.65 (s, 1H), 2.98(s, 3H). m/z [M+H]⁺ 398.0.

6-Bromo-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using6-bromo-1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.71 (s, 1H), 7.76 (d, J=9.4Hz, 1H), 7.62-7.52 (m, 3H), 6.52 (s, 1H), 3.00 (s, 3H). m/z [M+H]⁺432.0.

7-Cyclopropyl-4-((2,2-difluoroethyl)amino)-1-phenylquinazolin-2(1H)-onewas prepared by using 7-cyclopropyl-1-phenylquinazoline-2,4(1H,3H)-dioneand 2,2-difluoroethan-1-amine

¹H NMR (400 MHz, DMSO-d₆) δ=8.71 (t, J=4.0 Hz, 1H), 8.03 (d, J=6.8 Hz,1H), 7.60-7.57 (m, 2H), 7.52-7.49 (m, 1H), 7.27 (d, J=6.0 Hz, 2H), 6.84(d, J=6.0 Hz, 1H), 6.37-6.11 (m, 2H), 3.93-3.86 (m, 2H), 1.80-1.77 (m,1H), 0.95-0.91 (m, 2H), 0.58 (dd, J=4.0, 4.8 Hz, 2H). m/z [M+H]⁺ 342.35.

1-(3-Chloropyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(3-chloropyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ=9.22 (d, J=3.2 Hz, 1H), 8.83 (d, J=6.4 Hz,1H), 8.59 (dd, J=1.2, 3.6 Hz, 1H), 8.20 (dd, J=1.2, 6.4 Hz, 1H), 7.84(d, J=6.4 Hz, 1H), 7.59 (dd, J=3.6, 6.4 Hz, 1H), 3.04 (d, J=3.6 Hz, 3H).m/z [M+H]⁺ 356.36

4-(Methylamino)-1-(3-methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(3-methylpyridin-2-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ=8.50 (d, J=4.0 Hz, 1H), 8.14 (d, J=6.4 Hz,1H), 7.77 (d, J=5.2 Hz, 1H), 7.52 (br s, 1H), 7.40-7.38 (m, 1H), 7.28(s, 1H), 3.14 (d, J=4.0 Hz, 3H), 2.16 (s, 3H). m/z [M+H]⁺ 336.37.

7-Isopropyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one wasprepared by using7-isopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.63 (d, J=4.8 Hz, 1H), 8.37 (dd, J=8.2, 2.3Hz, 1H), 7.47 (t, J=7.6 Hz, 2H), 7.41-7.30 (m, 1H), 7.20 (d, J=8.1 Hz,1H), 7.15 (d, J=8.1, 1H), 2.98 (dd, J=4.5, 2.3 Hz, 4H), 2.81 (p, J=7.2Hz, 1H), 1.00 (dd, J=7.0, 2.3 Hz, 7H). m/z [M+H]⁺ 295.1

5-Fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using5-fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.20 (dd, J=12.4, 5.5 Hz, 1H), 7.62 (t,J=7.5 Hz, 2H), 7.58-7.50 (m, 2H), 7.35 (d, J=7.6 Hz, 2H), 6.36 (s, 1H),3.02 (s, 3H). m/z [M+H]⁺ 338.1.

6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-onewas prepared by using6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (s, 1H), 8.43 (s, 1H), 7.77-7.67 (m,1H), 7.56 (dt, J=7.1, 2.1 Hz, 2H), 7.45 (dt, J=6.6, 2.6 Hz, 1H), 5.75(s, 1H), 2.05 (d, J=8.0 Hz, 1H), 0.97 (d, J=8.2 Hz, 2H), 0.26 (s, 2H).m/z [M+H]⁺ 404.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrilewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrileand cyclopropylmethanamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (t, J=5.1 Hz, 1H), 8.76 (s, 1H), 7.74(d, J=7.3 Hz, 1H), 7.57 (d, J=7.0 Hz, 2H), 7.49 (d, J=7.5 Hz, 1H), 5.73(s, 1H), 2.18-2.10 (m, 1H), 1.22-1.15 (m, 1H), 1.08 (d, J=7.4 Hz, 2H),0.52 (d, J=6.8 Hz, 2H), 0.44-0.37 (m, 2H), 0.31 (d, J=3.9 Hz, 2H). m/z[M+H]⁺ 391.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((oxetan-2-ylmethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrilewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrileand oxetan-2-ylmethanamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.78 (s, 1H), 7.79-7.74 (m,1H), 7.60 (d, J=8.4 Hz, 2H), 7.52-7.46 (m, 1H), 5.74 (s, 1H), 5.01-4.92(m, 1H), 4.60-4.44 (m, 3H), 3.84 (d, J=15.7 Hz, 1H), 3.77-3.66 (m, 1H),3.50 (s, 1H), 2.14 (s, 1H), 1.07 (s, 2H), 0.40 (d, J=7.1 Hz, 2H). m/z[M+H]⁺ 407.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(methylsulfonyl)ethyl)amino)-2-oxo-1,2-dihydro-quinazoline-6-carbonitrilewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrileand 2-(methylsulfonyl)ethan-1-amine

¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=5.9 Hz, 1H), 8.66 (s, 1H), 7.75(dd, J=6.6, 3.2 Hz, 1H), 7.63-7.54 (m, 2H), 7.52-7.46 (m, 1H), 5.76 (s,1H), 3.91 (p, J=7.3 Hz, 2H), 3.59-3.49 (m, 2H), 3.09 (s, 3H), 2.20-2.09(m, 1H), 1.09 (d, J=8.4 Hz, 2H), 0.42 (d, J=6.4 Hz, 2H). m/z [M+H]⁺443.1.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1R,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione and(1R,2S)-2-fluorocyclopropan-1-amine

¹H NMR (400 MHz, Methanol-d₄) δ 8.02 (dd, J=8.6, 1.9 Hz, 1H), 7.59 (tdt,J=49.6, 6.1, 2.9 Hz, 4H), 6.95 (d, J=8.5 Hz, 1H), 6.17 (s, 1H),4.80-4.55 (m, 1H), 3.10 (dt, J=9.1, 6.3 Hz, 1H), 1.91-1.75 (m, 1H),1.40-1.23 (m, 2H), 1.02 (d, J=8.2 Hz, 2H), 0.62 (dp, J=4.8, 2.3 Hz, 2H).m/z [M+H]⁺ 370.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-fluorocyclopropyl)methyl)amino)-5-methoxyquinazolin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dioneand (1-fluorocyclopropyl)methanamine

¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (t, 1H), 7.71-7.69 (m, 1H), 7.55-7.53(m, 2H), 7.52-7.42 (m, 1H), 6.44 (d, J=1.5 Hz, 1H), 5.61 (d, J=1.5 Hz,1H), 4.02-3.94 (m, 5H), 1.81-1.77 (m, 1H), 1.10-1.03 (m, 2H), 0.94-0.92(m, 4H), 0.62-0.60 (m, 2H). m/z [M+H]⁺ 414.39.

4-Methoxy-1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting1-(2-methylpyridin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dioneand methanol

¹H NMR (500 MHz, DMSO-d₆): δ 8.66 (dd, J=1.5 Hz, 1H), 8.25 (d, J=8 Hz,1H), 7.84 (dd, J=1.5 Hz, 1H), 7.66 (dd, J=1.0 Hz, 1H), 7.53-7.50 (m,1H), 6.58 (s, 1H), 4.15 (s, 3H), 2.20 (s, 3H); LCMS. m/z [M+H]⁺ 336.40.

1-(2-Chlorophenyl)-4-cyclopropoxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneand cycloproanol

¹H NMR (500 MHz, DMSO-d₆) δ 8.58 (d, J=8.0 Hz, 1H), 7.79 (d, J=8.0 Hz,1H), 7.71-7.68 (m, 1H), 7.55-7.52 (m, 3H), 4.67-4.64 (m, 1H), 1.02-0.94(m, 4H). m/z [M+H]⁺ 382.33.

1-(2-Chlorophenyl)-4-(((S,S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(trifluoromethoxy)-quinazoline-2,4(1H,3H)-dione andtrans-2-fluorocyclopropan-1-amine

¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H),7.77-7.73 (m, 1H), 7.64-7.50 (m, 3H), 7.26 (d, J=10.0 Hz, 1H), 6.10 (s,1H), 4.96-4.82 (m, 1H), 3.48-3.42 (m, 1H), 1.55-1.47 (m, 1H), 1.24-1.19(m, 1H). m/z [M+H]⁺ 414.39.

1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-cyclopropyl-5-(difluoromethoxy)quinazoline-2,4(1H,3H)-dione

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.74-7.72 (m, 1H), 7.59-7.55 (m, 3H),7.45-7.28 (m, 1H), 6.56 (s, 1H), 5.87 (s, 1H), 3.01 (d, J=4.5 Hz, 3H),1.86-1.82 (m, 1H), 0.97-0.95 (m, 2H), 0.61-0.59 (m, 2H). m/z [M+H]⁺392.3.

7-Cyclopropyl-5-ethyl-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-5-ethyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (500 MHz, DMSO-d₆) δ ppm 7.45-7.35 (m, 3H), 7.19 (s, 1H),7.13-7.11 (m, 1H), 6.67 (s, 1H), 5.83 (d, J=1.5 Hz, 1H), 3.13 (q, J=7.5Hz, 2H), 3.00 (s, 3H), 1.91 (s, 3H), 1.74-1.70 (m, 1H), 1.23 (t, J=7.5Hz, 3H), 0.90-0.88 (m, 2H), 0.52-0.50 (m, 2H). m/z [M+H]⁺ 334.37.

1-(2-Chlorophenyl)-7-cyclopropyl-4-methoxyquinazolin-2(1H)-one wasprepared by using1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione andmethanol

¹H NMR (400 MHz, DMSO-d₆) δ 7.87 (d, J=8.5 Hz 1H), 7.78-7.75 (m, 1H),7.62-7.54 (m, 3H), 6.9 (dd, J=8.5, 1.5 Hz, 1H), 6.15 (d, J=1.5 Hz, 1H),4.08 (s, 3H), 1.92-1.87 (m, 1H), 0.99-0.96 (m, 2H), 0.66-0.64 (m, 2H).m/z [M+H]⁺ 327.16.

7-chloro-4-(methylamino)-1-(3-vinylphenyl)quinazolin-2(1H)-one wasprepared by using7-chloro-1-(3-vinylphenyl)quinazoline-2,4(1H,3H)-dione.

1-(2-Chlorophenyl)-4-(pyridin-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneand pyridin-4-amine

¹H NMR (400 MHz, DMSO-d₆) δ 9.14 (br s, 1H), 8.57 (d, J=5.3 Hz, 2H),8.07-7.77 (m, 3H), 7.68 (m, 1H), 7.52 (m, 3H). m/z [M+H]⁺ 418.00.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-onewas prepared by using7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione andisoxazol-4-amine

¹H NMR (400 MHz, DMSO-d₆) δ 10.71 (s, 1H), 9.46 (s, 1H), 8.89 (s, 1H),8.66 (s, 2H), 7.85-7.73 (m, 1H), 7.69-7.51 (m, 3H), 6.63 (s, 1H). m/z[M+H]⁺ 452.9 (major).

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(2-(trifluoromethyl)pyridin-3-yl)-quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dioneand cylcopropylmethanamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.77 (d, J=2.1 Hz, 1H), 8.53 (s, 1H),8.07-7.88 (m, 2H), 7.84 (d, J=6.7 Hz, 1H), 6.70 (d, J=8.5 Hz, 1H), 5.91(s, 1H), 1.73 (s, 1H), 1.05 (s, 1H), 0.81 (d, J=8.7 Hz, 2H), 0.47 (m,2H), 0.35 (d, J=7.8 Hz, 2H), 0.16 (s, 2H). m/z [M+H]⁺ 399.1.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(2-(difluoromethoxy)pyridin-3-yl)-quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dioneand cylcopropylmethanamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.41 (d, J=4.8 Hz, 1H), 8.09(d, J=8.3 Hz, 1H), 7.99 (d, J=7.9 Hz, 1H), 7.74 (t, J=73.3, Hz, 1H),7.50 (m, 1H), 6.86 (d, J=8.2 Hz, 1H), 6.15 (s, 1H), 1.88 (s, 1H), 1.20(s, 1H), 0.96 (d, J=8.6 Hz, 2H), 0.63 (d, J=14.2 Hz, 2H), 0.49 (d, J=7.8Hz, 2H), 0.30 (d, J=4.5 Hz, 2H). m/z [M+H]⁺ 401.1

1-(2-chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione andtrans-2-fluorocyclopropan-1-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (s, 1H), 8.23 (d, J=9.1 Hz, 1H), 7.75(s, 1H), 7.58 (s, 2H), 7.51 (s, 1H), 7.24 (d, J=9.0 Hz, 1H), 6.10 (s,1H), 1.52 (m, 1H), 1.22 (m, 1H), two missing protons under DMSO peak.m/z [M+H]⁺ 414.0.

1-(2-Chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione andcylcopropylmethanamine

¹H NMR (400 MHz, Methanol-d₄) δ 8.06 (d, J=8.4 Hz, 1H), 7.60-7.48 (m,1H), 7.40 (dt, J=6.2, 2.3 Hz, 2H), 7.26 (dd, J=16.4, 7.1 Hz, 2H), 6.36(s, 1H), 3.42-3.23 (m, 2H), 1.63 (t, J=18.4 Hz, 3H), 1.12 (m, 1H), 0.40(d, J=7.7 Hz, 2H), 0.19 (d, J=5.3 Hz, 2H). m/z [M+H]⁺ 390.1.

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione and(1S,2R)-2-fluorocyclopropan-1-amine

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.46 (d, J=8.5 Hz, 1H),7.69-7.49 (m, 4H), 7.37 (d, J=7.2 Hz, 2H), 6.57 (s, 1H), 5.01-4.73 (m,1H), 1.45-1.17 (m, 2H). m/z [M+H]⁺ 364.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one wasprepared by substituting1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, DMSO-d₆) δ 8.51 (s, 1H), 8.07-7.93 (m, 1H), 7.73 (dt,J=5.9, 2.8 Hz, 1H), 7.62-7.39 (m, 3H), 6.82 (d, J=8.5 Hz, 1H), 6.02 (s,1H), 2.97 (t, J=3.1 Hz, 3H), 1.81 (s, 1H), 0.94 (d, J=8.4 Hz, 2H), 0.60(s, 2H). m/z [M+H]⁺ 326.0.

(R)-4-(2-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting (R)-azetidin-2-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=8.1 Hz, 1H), 7.61 (dd, J=8.2, 2.4Hz, 1H), 7.40-7.25 (m, 3H), 7.12 (d, J=7.5 Hz, 1H), 5.26 (s, 1H),4.94-4.50 (m, 3H), 3.96 (d, J=11.5 Hz, 1H), 3.70 (dd, J=11.9, 3.3 Hz,2H), 2.57-2.46 (s, 1H), 2.43-2.31 (s, 1H), 1.92 (d, J=16.3, 3H). m/z[M+H]⁺ 391.1

N-Methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-amino-N-methylethane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (s, 1H), 8.79 (d, J=8.2 Hz, 1H), 7.80(d, J=8.1 Hz, 1H), 7.38-7.24 (m, 3H), 7.17 (s, 1H), 7.16 (d, J=7.7 Hz,1H), 3.86 (d, J=20.3 Hz, 2H), 3.52-3.26 (m, 2H), 2.64 (s, 3H), 1.93 (s,3H). m/z [M+H]⁺ 442.1

N-Methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)propane-1-sulfonamidewas prepared by substituting 3-amino-N-methylpropane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.85 (d, J=7.2 Hz, 1H), 7.78(d, J=8.2 Hz, 1H), 7.35-7.27 (m, 3H), 7.16 (d, J=7.5 Hz, 1H), 6.98 (s,1H), 3.74-3.58 (m, 2H), 3.20-3.12 (m, 2H), 2.59 (d, J=2.5 Hz, 3H),2.11-2.0 (m, 2H), 1.93 (d, J=2.5 Hz, 3H). m/z [M+H]⁺ 456.1

N-Cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-amino-N-cyclopropylethane-1-sulfonamideand1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.78 (d, J=7.3 Hz, 1H), 7.81(d, J=8.1 Hz, 1H), 7.67 (s, 1H), 7.40-7.25 (m, 3H), 7.16 (d, J=7.6 Hz,1H), 3.93-3.81 (m, 2H), 3.55-2.45 (m, 2H), 2.59-2.51 (m, 1H), 1.93 (d,J=2.6 Hz, 3H), 0.60 (t, J=3.3 Hz, 4H). m/z [M+H]⁺ 468.1

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine HCl and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.91 (d, J=7.1 Hz, 1H), 7.79(d, J=8.6 Hz, 1H), 7.39-7.27 (m, 3H), 7.18 (t, J=7.9 Hz, 1H), 4.91 (d,J=64.8 Hz, 1H), 3.15-3.09 (m, 1H), 1.93 (s, 3H), 1.42-1.22 (m, 2H). m/z[M+H]⁺ 379.1

4-(((1R,2S)-2-Fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting (1R,2S)-2-fluorocyclopropan-1-amine HCl and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.99 (s, 1H), 8.91 (d, J=7.1 Hz, 1H), 7.79(d, J=8.6 Hz, 1H), 7.39-7.27 (m, 3H), 7.18 (t, J=7.9 Hz, 1H), 4.91 (d,J=64.8 Hz, 1H), 3.15-3.09 (m, 1H), 1.93 (s, 3H), 1.42-1.22 (m, 2H). m/z[M+H]⁺ 379.1

N,N-Dimethyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamidewas prepared by substituting 3-amino-N,N-dimethylpropane-1-sulfonamideand 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) (8.87 (s, 1H), 8.44 (d, J=7.7 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.53-7.36 (m, 3H), 7.26 (d, J=7.4 Hz, 1H), 6.45 (s,1H), 3.75-3.56 (m, 2H), 3.21 (t, J=7.1 Hz, 2H), 2.80 (d, J=2.5 Hz, 6H),2.15-2.03 (m, 2H), 1.95 (d, J=2.5 Hz, 3H). m/z [M+H]⁺ 469.1

N,N-Dimethyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-amino-N,N-dimethylethane-1-sulfonamideand 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) (9.05 (s, 1H), 8.37 (d, J=8.5 Hz, 1H), 7.63(d, J=8.4 Hz, 1H), 7.50-7.40 (m, 3H), 7.26 (d, J=7.5 Hz, 1H), 6.46 (s,1H), 4.01-3.84 (m, 2H), 3.49-3.42 (m, 2H), 2.83 (s, 6H), 1.96 (d, J=2.6Hz, 3H). m/z [M+H]⁺ 455.1

tert-Butyl(R)-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)pyrrolidine-1-carboxylatewas prepared by substituting tert-butyl(R)-3-aminopyrrolidine-1-carboxylate and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

4-((2-(Morpholinosulfonyl)ethyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 2-(morpholinosulfonyl)ethan-1-amine and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (s, 1H), 8.37 (d, J=8.5 Hz, 1H), 7.63(d, J=8.3 Hz, 1H), 7.52-7.38 (m, 3H), 7.25 (d, J=7.5 Hz, 1H), 6.46 (s,1H), 4-3.84 (m, 2H), 3.65 (s, 4H), 3.55-3.46 (m, 2H), 3.25-3.14 (m, 4H),1.96 (s, 3H). m/z [M+H]⁺ 497.1

N-cyclopropyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-amino-N-cyclopropylethane-1-sulfonamideand 1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.02 (s, 1H), 8.35 (d, J=8.7 Hz, 1H), 7.65(s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.52-7.38 (m, 3H), 7.25 (d, J=7.5 Hz,1H), 6.46 (s, 1H), 3.95-3.78 (m, 2H), 3.60-3.43 (m, 3H), 2.57 (d, J=6.4Hz, 1H), 1.96 (d, J=2.7 Hz, 3H), 0.60 (t, J=3.9 Hz, 4H). m/z [M+H]⁺467.1

(R)-4-(2-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (R)-azetidin-2-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.15-8.06 (m, 1H), 7.54-7.37 (m, 4H), 7.22(d, J=7.3 Hz, 1H), 6.44 (d, J=7.1 Hz, 1H), 5.29 (s, 1H), 4.98-4.44 (m,3H), 3.99-3.88 (m, 1H), 3.71 (d, J=11.8 Hz, 1H), 2.57-2.45 (m, 1H),2.40-2.27 (m, 1H), 1.95 (dd, J=16.3, 2.6 Hz, 3H). m/z [M+H]⁺ 390.1

4-(3-(Hydroxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting azetidin-3-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.10 (d, J=8.5 Hz, 1H), 7.53-7.38 (m, 4H),7.22 (d, J=7.3 Hz, 1H), 6.44 (s, 1H), 5.07-4.79 (m, 2H), 4.65-4.48 (m,1H), 4.37-4.23 (m, 1H), 4.13-3.99 (m, 1H), 3.69-3.60 (m, 2H), 2.96-2.86(m, 1H), 1.94 (s, 3H). m/z [M+H]⁺ 390.1

(R)-4-(2-(Methoxymethyl)azetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (R)-2-(methoxymethyl)azetidine and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=8.5 Hz, 1H), 7.56-7.38 (m, 4H),7.23 (t, J=7.6 Hz, 1H), 6.45 (d, J=7.0 Hz, 1H), 5.03-4.68 (m, 2H),4.64-4.40 (m, 1H), 3.96-3.86 (m, 1H), 3.71-3.62 (m, 2H), 2.61-2.50 (m,1H), 2.45-2.30 (m, 1H), 1.95 (d, J=17.4 Hz, 3H). m z [M+H]⁺ 404.1

4-((trans)-3,4-Dihydroxypyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (3S,4S)-pyrrolidine-3,4-diol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.51-8.37 (m, 1H), 7.53-7.39 (m, 4H), 7.25(dd, J=24.0, 7.5 Hz, 1H), 6.47 (d, J=16.7 Hz, 1H), 5.40 (s, 2H),4.54-3.85 (m, 4H), 3.82-3.54 (m, 2H), 1.95 (d, J=34.0, 3H). m/z [M+H]⁺406.1

4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine HCl and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.51 (d, J=8.5 Hz, 1H), 7.61(d, J=8.4 Hz, 1H), 7.53-7.38 (m, 3H), 7.28 (t, J=8.9 Hz, 1H), 6.47 (s,1H), 4.90 (d, J=65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.96 (s, 3H), 1.49-1.18(m, 2H). m/z [M+H]⁺ 378.1

4-(((1S,2R)-2-fluorocyclopropyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1R,2S)-2-fluorocyclopropan-1-amine HCl and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (s, 1H), 8.51 (d, J=8.5 Hz, 1H), 7.61(d, J=8.4 Hz, 1H), 7.53-7.38 (m, 3H), 7.28 (t, J=8.9 Hz, 1H), 6.47 (s,1H), 4.90 (d, J=65.0 Hz, 1H), 3.15-3.05 (m, 1H), 1.96 (s, 3H), 1.49-1.18(m, 2H). m/z [M+H]⁺ 378.1

3-((2-Oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamidewas prepared by substituting 3-aminopropane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (bs, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.56(d, J=8.4 Hz, 1H), 7.50-7.37 (m, 3H), 7.21 (d, J=7.5 Hz, 1H), 6.66 (bs,2H), 6.44 (s, 1H), 4.00-3.50 (m, 2H), 3.11 (t, J=8.0 Hz, 2H), 2.09 (t,J=8.0, 2H), 1.92 (s, 3H). m/z [M+H]⁺ 441.1

N-Methyl-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamidewas prepared by substituting 3-(methylamino)propane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (bs, 1H), 8.34 (d, J=8.5 Hz, 1H), 7.56(d, J=8.5 Hz, 1H), 7.49-7.37 (m, 3H), 7.21 (d, J=8.5 Hz, 1H), 6.68 (s,1H), 6.44 (s, 1H), 4.0-3.5 (m, 2H), 3.13 (t, J=7.9 Hz, 1H), 2.57 (s,3H), 2.03 (t, J=7.9 Hz, 1H), 1.92 (s, 3H). m/z [M+H]⁺ 455.1

2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-aminoethane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (bs, 1H), 8.29 (d, J=8.2 Hz, 1H), 7.58(d, J=8.3 Hz, 1H), 7.50-7.39 (m, 3H), 7.21 (d, J=7.4 Hz, 2H), 7.03 (bs,1H), 6.67 (bs, 1H), 6.45 (s, 1H), 4.00-3.70 (m, 2H), 3.50-3.35 (m, 2H),1.93 (s, 3H). m/z [M+H]⁺ 427.05

N-methyl-2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-(methylamino)ethane-1-sulfonamide and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.29 (d, J=8.1 Hz, 1H), 7.58(d, J=8.5 Hz, 1H), 7.52-7.38 (m, 3H), 7.21 (d, J=7.5 Hz, 1H), 6.67 (bs,1H), 6.45 (s, 1H), 4.00-3.75 (m, 2H), 3.48-3.34 (m, 2H), 2.62 (s, 3H),1.92 (s, 3H). m/z [M+H]⁺ 441.1

(S)-4-(2-(Hydroxymethyl)morpholino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (S)-morpholin-2-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.14 (d, J=8.5 Hz, 1H), 7.54-7.38 (m, 4H),7.31-7.24 (m, 1H), 6.51 (s, 1H), 4.91 (bs, 1H), 4.43-4.16 (m, 2H),4.00-3.93 (m, 1H), 3.79-3.59 (m, 2H), 3.56-3.45 (m, 2H), 3.34-3.09 (m,2H), 1.94 (s, 3H). m/z [M+H]⁺ 420.1

4-(3-Methoxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 3-methoxyazetidine and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.09 (d, J=8.5 Hz, 1H), 7.52-7.39 (m, 3H),7.22 (d, J=7.4 Hz, 1H), 6.45 (s, 1H), 5.14-4.46 (m, 3H), 4.42-4.36 (m,1H), 4.28-3.98 (m, 1H), 3.32 (s, 3H), 1.94 (s, 3H). m/z [M+H]⁺ 390.1

4-(4-methyl-3-oxopiperazin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 1-methylpiperazin-2-one and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J=8.4 Hz, 1H), 7.56-7.40 (m, 4H),7.26 (d, J=7.6 Hz, 1H), 6.50 (s, 1H), 4.49-4.35 (m, 2H), 4.21-4.09 (m,1H), 4.08-3.99 (m, 2H), 2.93 (s, 3H), 1.95 (s, 3H). m/z [M+H]⁺ 417.1

4-(3-Hydroxyazetidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting azetidin-3-ol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.08 (d, J=8.7 Hz, 1H), 7.52-7.37 (m, 4H),7.22 (d, J=7.3 Hz, 1H), 6.45 (s, 1H), 6.01 (bs, 1H), 5.15-4.85 (m, 1H),4.69-4.39 (m, 3H), 4.22-3.90 (m, 1H), 1.94 (s, 3H). m/z [M+H]⁺ 376.1

1-(2-Oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)azetidine-3-carbonitrilewas prepared by substituting azetidine-3-carbonitrile and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.02 (d, J=8.3 Hz, 1H), 7.55-7.37 (m, 4H),7.22 (d, J=7.4 Hz, 1H), 6.47 (s, 1H), 5.31-4.45 (m, 4H), 4.09-3.98 (m,1H), 1.94 (s, 3H). m/z [M+H]⁺ 385.1

(3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamidewas prepared by substituting1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.42 (d, J=8.2 Hz, 1H), 7.59(d, J=8.4 Hz, 1H), 7.52-7.37 (m, 3H), 7.25 (d, J=7.5 Hz, 1H), 6.61 (bs,1H), 6.54 (bs, 2H), 6.44 (s, 1H), 3.67-3.49 (m, 2H), 3.02-2.97 (m, 2H),1.95 (s, 3H), 1.89 (t, J=7.3 Hz, 2H). m/z [M+H]⁺ 456.1

(2-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)ethyl)sulfamidewas prepared by substituting1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (bs, 1H), 8.40 (d, J=8.4 Hz, 1H), 7.60(d, J=8.4 Hz, 1H), 7.52-7.38 (m, 3H), 7.24 (d, J=7.5 Hz, 1H), 6.74 (bs,1H), 6.62 (bs, 2H), 6.45 (s, 1H), 3.76-3.60 (m, 2H), 3.27-3.13 (m, 2H),1.95 (s, 3H). m/z [M+H]⁺ 442.1

3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propane-1-sulfonamidewas prepared 3-aminopropane-1-sulfonamide and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione bysubstituting.

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.73(dd, J=6.0, 3.2 Hz, 1H), 7.56 (dt, J=5.9, 3.0 Hz, 2H), 7.46 (d, J=7.7Hz, 1H), 6.83 (d, J=5.7 Hz, 3H), 6.03 (s, 1H), 3.72-3.50 (m, 2H), 3.09(t, J=8.2 Hz, 2H), 2.07 (t, J=7.9 Hz, 2H), 1.87-1.76 (m, 1H), 0.95 (d,J=8.4 Hz, 2H), 0.65-0.53 (m, 2H). m/z [M+H]⁺ 433.1

3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropane-1-sulfonamidewas prepared by substituting 3-amino-N-methylpropane-1-sulfonamide and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=5.4 Hz, 1H), 8.08-7.98 (m, 1H),7.73 (dt, J=6.2, 3.0 Hz, 1H), 7.56 (dt, J=6.2, 3.1 Hz, 2H), 7.47 (dt,J=5.8, 3.1 Hz, 1H), 6.96 (d, J=4.7 Hz, 1H), 6.83 (d, J=8.5 Hz, 1H), 6.03(s, 1H), 3.71-3.50 (m, 2H), 3.17-3.08 (m, 2H), 2.58 (t, J=3.8 Hz, 3H),2.03 (q, J=7.5 Hz, 2H), 1.88-1.75 (m, 1H), 0.94 (d, J=8.4 Hz, 2H),0.66-0.52 (m, 2H). m/z [M+H]⁺ 447.0.

2-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)ethane-1-sulfonamidewas prepared by substituting 2-aminoethane-1-sulfonamide and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (s, 1H), 8.01-7.91 (m, 1H), 7.73 (d,J=5.9 Hz, 1H), 7.56 (dd, J=6.3, 3.3 Hz, 2H), 7.47 (s, 1H), 7.01 (s, 2H),6.84 (d, J=8.2 Hz, 1H), 6.04 (s, 1H), 3.96-3.81 (m, 2H), 3.40 (s, 2H),1.90-1.76 (m, 1H), 0.95 (d, J=8.3 Hz, 2H), 0.65-0.53 (m, 2H). m/z [M+H]⁺419.0.

2-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylethane-1-sulfonamidewas prepared by substituting 2-amino-N-methylethane-1-sulfonamide and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.62 (d, J=7.0 Hz, 1H), 8.00-7.91 (m, 1H),7.74 (dt, J=6.4, 3.0 Hz, 1H), 7.56 (dq, J=7.0, 3.5 Hz, 2H), 7.47 (dt,J=6.1, 3.2 Hz, 1H), 7.10 (d, J=5.0 Hz, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.04(s, 1H), 3.90-3.72 (m, 2H), 3.42 (t, J=6.5 Hz, 2H), 2.63 (t, J=3.8 Hz,3H), 1.87-1.76 (m, 1H), 0.95 (d, J=8.4 Hz, 2H), 0.68-0.53 (m, 2H). m z[M+H]⁺ 433.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-(4-(hydroxymethyl)piperidin-1-yl)quinazolin-2(1H)-onewas prepared by substituting piperidin-4-ylmethanol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 7.76-7.65 (m 2H), 7.57 (dt, J=5.9, 2.5 Hz,2H), 7.47 (dt, J=5.8, 2.6 Hz, 1H), 6.81 (d, J=8.4 Hz, 1H), 6.06 (s, 1H),4.63 (s, 1H), 4.39-4.28 (m, 2H), 3.34 (s, 2H), 3.15 (d, J=15.0 Hz, 2H),1.87-1.78 (m, 1H), 1.82 (d, J=13.0 Hz, 3H), 1.75 (s, 1H), 1.36 (q,J=12.7, 12.3 Hz, 2H), 0.96 (d, J=8.5 Hz, 2H), 0.65-0.50 (m, 2H). m/z[M+H]⁺ 410.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-(3-hydroxypiperidin-1-yl)quinazolin-2(1H)-onewas prepared by substituting piperidin-3-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 7.80 (t, J=9.4 Hz, 1H), 7.73 (dt, J=5.9, 2.6Hz, 1H), 7.65-7.53 (m, 2H), 7.50-7.43 (m, 1H), 6.81 (d, J=8.5 Hz, 1H),6.06 (s, 1H), 4.04 (t, J=10.8 Hz, 1H), 3.90-3.68 (m, 2H), 3.37-3.23 (m,2H), 2.00-1.78 (m, 3H), 1.56 (dq, J=19.3, 9.5 Hz, 2H), 0.96 (d, J=8.6Hz, 2H), 0.69-0.51 (m, 2H). m/z [M+H]⁺ 396.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-(3-hydroxyazetidin-1-yl)quinazolin-2(1H)-onewas prepared by substituting azetidin-3-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 7.72 (dd, J=6.9, 3.1 Hz, 2H), 7.56 (dt,J=5.6, 2.5 Hz, 2H), 7.42 (d, J=2.5 Hz, 1H), 6.78 (d, J=8.4 Hz, 1H), 6.03(s, 1H), 5.96 (bs, 1H), 5.09-4.72 (m, 1H), 4.74-3.88 (m, 3H), 4.68-4.57(m, 1H), 1.88-1.73 (m, 1H), 0.95 (d, J=8.4 Hz, 2H), 0.64-0.46 (m, 2H).m/z [M+H]⁺ 368.1.

(3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamidewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.48 (d, J=5.9 Hz, 1H), 8.02 (d, J=8.8 Hz,1H), 7.72 (dt, J=6.1, 2.8 Hz, 1H), 7.56 (dt, J=5.9, 2.8 Hz, 2H), 7.45(dt, J=6.0, 2.8 Hz, 1H), 6.82 (d, J=8.4 Hz, 1H), 6.58 (d, J=6.3 Hz, 1H),6.52 (s, 2H), 6.02 (s, 1H), 3.47-3.27 (m, 2H), 2.98 (d, J=6.8 Hz, 2H),1.91-1.76 (m, 3H), 0.94 (d, J=8.4 Hz, 2H), 0.65-0.52 (m, 2H). m/z [M+H]⁺448.1

(3-((1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)propyl)sulfamidewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.73(dt, J=6.1, 2.8 Hz, 1H), 7.56 (dt, J=6.0, 2.8 Hz, 2H), 7.50-7.43 (m,1H), 6.83 (d, J=8.6 Hz, 2H), 6.76 (t, J=6.3 Hz, 1H), 6.62 (s, 2H), 6.02(s, 1H), 3.75-3.54 (m, 2H), 3.18 (d, J=6.5 Hz, 2H), 1.84-1.75 (m, 1H),0.95 (d, J=8.3 Hz, 2H), 0.64-0.53 (m, 2H). m/z [M+H]⁺ 434.0

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethyl)pyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-(difluoromethyl)pyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (t, J=4.2 Hz, 1H), 8.39 (d, J=8.6 Hz,1H), 8.21 (s, 2H), 7.78 (dt, J=6.1, 3.2 Hz, 1H), 7.64-7.52 (m, 3H), 6.96(s, 2H), 6.95 (d, J=112 Hz, 1H), 6.13 (s, 1H), 1.94-1.83 (m, 1H), 1.00(d, J=8.4 Hz, 2H), 0.71-0.59 (m, 2H). m/z [M+H]⁺ 439.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-cyclopropylpyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-(cyclopropyl)pyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.45-8.29 (m, 2H), 7.95-7.71(m, 3H), 7.66-7.49 (m, 3H), 6.95 (d, J=8.4 Hz, 1H), 6.12 (s, 1H),2.10-1.99 (m, 1H), 1.94-1.82 (m, 1H), 1.06-0.83 (m, 6H), 0.70-0.57 (m,2H). m/z [M+H]⁺ 429.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-(difluoromethoxy)pyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-(difluoromethoxy)pyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.25 (bs, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.19(d, J=5.7 Hz, 1H), 8.17 (d, J=212 Hz, 1H), 7.81-7.70 (m, 2H), 7.64-7.48(m, 3H), 6.96 (d, J=8.5 Hz, 1H), 6.13 (s, 1H), 1.97-1.82 (m, 1H), 1.00(d, J=8.4 Hz, 2H), 0.72-0.54 (m, 2H). m z [M+H]⁺ 455.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methyl-1,2,4-oxadiazol-5-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 3-methyl-1,2,4-oxadiazol-5-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (bs, 1H), 8.26 (dd, J=8.3, 2.6 Hz,1H), 7.82 (d, J=7.0 Hz, 1H), 7.71-7.62 (m, 3H), 6.98 (d, J=8.4 Hz, 1H),6.16 (s, 1H), 2.36 (d, J=2.7 Hz, 3H), 1.97-1.84 (m, 1H), 1.02 (d, J=8.1Hz, 2H), 0.73-0.54 (m, 2H). m/z [M+H]⁺ 394.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((oxazol-5-ylmethyl)amino)quinazolin-2(1H)-onewas prepared by substituting oxazol-5-ylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (bs, 1H), 8.34 (s, 1H), 8.08 (d, J=8.5Hz, 1H), 7.74 (bs, 1H), 7.56 (bs, 2H), 7.48 (bs, 1H), 7.13 (bs, 1H),6.84 (d, J=8.5 Hz, 1H), 6.04 (s, 1H), 4.90-4.63 (m, 2H), 1.89-1.77 (m,1H), 0.95 (d, J=8.3 Hz, 2H), 0.67-0.54 (m, 2H). m z [M+H]⁺ 393.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)quinazolin-2(1H)-onewas prepared by substituting isoxazol-3-ylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (bs, 1H), 8.88 (s, 1H), 8.08 (dd,J=8.5, 2.6 Hz, 1H), 7.72 (bs, 1H), 7.60-7.53 (m, 2H), 7.48 (bs, 1H),6.85 (d, J=8.5 Hz, 1H), 6.60 (s, 1H), 6.06 (s, 1H), 4.95-4.70 (m, 2H),1.87-1.78 (m, 1H), 0.95 (d, J=8.3 Hz, 2H), 0.69-0.52 (m, 2H). m/z [M+H]⁺393.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-3-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 5-methylisoxazol-3-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.97 (bs, 1H), 8.32 (bs, 1H), 7.77 (bs,1H), 7.70-7.51 (m, 3H), 6.90 (d, J=8.5 Hz, 1H), 6.68 (bs, 1H), 6.09 (s,1H), 2.44 (s, 3H), 1.93-1.81 (m, 1H), 0.98 (d, J=8.4 Hz, 2H), 0.73-0.55(m, 2H). m/z [M+H]⁺ 393.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-4-yl)methyl)amino)quinazolin-2(1H)-onewas prepared by substituting (1-methyl-1H-pyrazol-4-yl)methanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (bs, 1H), 8.06 (dd, J=8.6, 2.5 Hz, 1H),7.73 (bs, 1H), 7.67 (d, J=2.6 Hz, 1H), 7.60-7.51 (m, 2H), 7.49-7.38 (m,2H), 6.81 (d, J=8.4 Hz, 1H), 6.02 (s, 1H), 4.66-4.41 (m, 2H), 3.80 (s,3H), 1.85-1.75 (m, 1H), 0.94 (d, J=8.0 Hz, 2H), 0.64-0.52 (m, 2H). m/z[M+H]⁺ 406.1

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-3-ylamino)quinazolin-2(1H)-onewas prepared by substituting isoxazol-3-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.86 (s, 1H), 8.32 (d, J=8.0 Hz, 1H), 7.77(bs, 1H), 7.66-7.53 (m, 3H), 6.90 (bs, 1H), 6.89 (d, J=8.6 Hz, 1H), 6.08(s, 1H), 1.91-1.81 (t, J=6.7 Hz, 1H), 0.97 (d, J=8.4 Hz, 2H), 0.69-0.56(m, 2H). m/z [M+H]⁺ 379.05

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methoxypyridin-3-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 5-methoxypyridin-3-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.07 (bs, 1H), 8.68 (bs, 1H), 8.36 (d,J=8.4 Hz, 1H), 8.13 (s, 1H), 7.98 (bs, 1H), 7.76 (bs, 1H), 7.65-7.51 (m,3H), 6.94 (d, J=8.4 Hz, 1H), 6.11 (s, 1H), 3.87 (s, 3H), 1.93-1.81 (m,1H), 0.99 (d, J=8.4 Hz, 2H), 0.70-0.57 (m, 2H). m z [M+H]⁺ 419.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((6-methylpyridin-3-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 6-methylpyridin-3-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.79 (s, 1H), 8.34 (d, J=8.5Hz, 1H), 8.14 (d, J=8.1 Hz, 1H), 7.75 (s, 1H), 7.64-7.46 (m, 3H), 7.31(d, J=8.4 Hz, 1H), 6.93 (d, J=8.5 Hz, 1H), 6.10 (s, 1H), 2.48 (s, 3H),1.91-1.81 (m, 1H), 0.98 (d, J=8.3 Hz, 2H), 0.71-0.56 (m, 2H). m/z [M+H]⁺403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((6-methoxypyridin-3-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 6-methoxypyridin-3-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.98 (s, 1H), 8.47 (s, 1H), 8.30 (d, J=8.5Hz, 1H), 8.07 (d, J=8.9 Hz, 1H), 7.75 (dd, J=6.3, 3.2 Hz, 1H), 7.62-7.46(m, 3H), 6.92 (t, J=7.6 Hz, 2H), 6.10 (s, 1H), 3.88 (s, 3H), 1.92-1.81(m, 1H), 0.98 (d, J=8.2 Hz, 2H), 0.70-0.55 (m, 2H). m z [M+H]⁺ 419.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-4-ylmethyl)amino)quinazolin-2(1H)-onewas prepared by substituting pyridin-4-ylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.13 (s, 1H), 8.54 (s, 2H), 8.13 (dd, J=8.6,2.6 Hz, 1H), 7.76-7.68 (m, 1H), 7.55 (d, J=3.2 Hz, 2H), 7.52-7.43 (m,1H), 7.36 (s, 2H), 6.87 (d, J=8.3 Hz, 1H), 6.06 (s, 1H), 4.91-4.65 (m,2H), 1.88-1.78 (m, 1H), 0.96 (d, J=8.3 Hz, 2H), 0.69-0.52 (m, 2H). m/z[M+H]⁺ 403.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-3-ylmethyl)amino)quinazolin-2(1H)-onewas prepared by substituting pyridin-3-ylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.63 (s, 1H), 8.49 (s, 1H),8.09 (dd, J=8.5, 2.5 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.73 (d, J=3.2 Hz,1H), 7.61-7.51 (m, 2H), 7.48 (d, J=3.2 Hz, 1H), 7.42-7.36 (m, 1H), 6.85(d, J=8.4 Hz, 1H), 6.04 (s, 1H), 4.89-4.65 (m, 2H), 1.87-1.76 (m, 1H),0.95 (d, J=8.3 Hz, 2H), 0.66-0.54 (m, 2H). m/z [M+H]⁺ 403.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2(1H)-onewas prepared by substituting pyridin-2-ylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.54 (d, J=3.6 Hz, 1H), 8.15(dd, J=8.6, 2.6 Hz, 1H), 7.84-7.68 (m, 2H), 7.58-7.52 (m, 2H), 7.46 (s,1H), 7.38 (d, J=8.0 Hz, 1H), 7.30 (s, 1H), 6.86 (d, J=8.5 Hz, 1H), 6.05(s, 1H), 4.95-4.72 (m, 2H), 1.89-1.77 (m, 1H), 0.96 (d, J=8.3 Hz, 2H),0.66-0.54 (m, 2H). m/z [M+H]⁺ 403.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyrimidin-5-ylamino)quinazolin-2(1H)-onewas prepared by substituting pyrimidin-5-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 2H), 8.94 (s, 1H), 8.29 (d, J=8.5Hz, 1H), 7.81-7.69 (m, 1H), 7.62-7.55 (m, 2H), 7.56-7.48 (m, 1H), 6.94(d, J=8.4 Hz, 1H), 6.76 (s, 2H), 6.09 (s, 1H), 1.91-1.82 (m, 1H), 0.99(d, J=8.3 Hz, 2H), 0.69-0.58 (m, 2H). m/z [M+H]⁺ 390.05

1-(2-Chlorophenyl)-7-isopropyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-7-isopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.40 (dd, J=8.1, 2.2 Hz, 1H),7.65-7.55 (m, 1H), 7.50-7.40 (m, 2H), 7.41-7.33 (m, 1H), 7.17 (dd,J=8.1, 2.3 Hz, 1H), 2.99 (s, 3H), 2.86-2.77 (m, 1H), 1.02-0.99 (m, 6H).m/z [M+H]⁺ 329.1

1-(2-Chlorophenyl)-7-(difluoromethyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-7-(difluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.26 (d, J=8.3 Hz, 1H),7.79-7.71 (m, 1H), 7.61-7.54 (m, 2H), 7.54-7.48 (m, 1H), 7.41 (d, J=8.3Hz, 1H), 7.00 (td, J=55.3, 2.2 Hz, 1H), 6.46 (s, 1H), 3.01 (s, 3H). m/z[M+H]⁺ 336.0

1-(2-Chlorophenyl)-7-isopropyl-4-(methylamino)quinazolin-2(1H)-one wasprepared by substituting1-(2-chlorophenyl)-7-isopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (s, 1H), 8.03 (d, J=7.0 Hz, 1H),7.78-7.66 (m, 1H), 7.60-7.51 (m, 2H), 7.48-7.41 (m, 1H), 7.15 (d, J=8.3Hz, 1H), 6.09 (s, 1H), 2.98 (s, 3H), 2.76 (p, J=6.6 Hz, 1H), 1.05 (d,J=6.7 Hz, 6H). m/z [M+H]⁺ 328.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyridin-3-ylamino)quinazolin-2(1H)-onewas prepared by substituting 3-amino pyridine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.08 (s, 1H), 8.96 (s, 1H), 8.43-8.19 (m,3H), 7.80-7.71 (m, 1H), 7.64-7.40 (m, 4H), 6.94 (d, J=8.4 Hz, 1H), 6.11(s, 1H), 1.91-1.81 (m, 1H), 0.99 (d, J=8.3 Hz, 2H), 0.69-0.58 (m, 2H).m/z [M+H]⁺ 389.05

1-(2-Chlorophenyl)-7-cyclopropyl-4-(pyridin-4-ylamino)quinazolin-2(1H)-onewas prepared by substituting 4-amino pyridine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.09 (s, 1H), 8.53 (s, 2H), 8.39 (d, J=8.5Hz, 1H), 8.03 (bs, 2H), 7.83-7.73 (m, 1H), 7.64-7.49 (m, 3H), 6.96 (d,J=8.4 Hz, 1H), 6.13 (s, 1H), 1.92-1.83 (m, 1H), 1.00 (d, J=8.3 Hz, 2H),0.69-0.60 (m, 2H). m/z [M+H]⁺ 389.05.

4-((1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazolin-4-yl)amino)picolinonitrilewas prepared by substituting 4-aminopicolinonitrile and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.64 (d, J=5.7 Hz, 1H), 8.44 (s, 1H), 8.31(d, J=8.5 Hz, 1H), 8.07 (s, 1H), 7.81-7.74 (m, 1H), 7.66-7.50 (m, 3H),6.95 (d, J=8.5 Hz, 1H), 6.12 (s, 1H), 1.92-1.83 (m, 1H), 0.99 (d, J=8.4Hz, 2H), 0.69-0.58 (m, 2H). m/z [M+H]⁺ 414.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-methoxypyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-methoxypyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.00 (s, 1H), 8.36 (bs, 1H), 8.16-8.01 (m,1H), 7.84-7.73 (m, 1H), 7.67-7.49 (m, 5H), 6.95 (d, J=8.3 Hz, 1H), 6.12(s, 1H), 3.86, 4H), 1.93-1.82 (m, 1H), 0.99 (d, J=8.5 Hz, 2H), 0.70-0.52(m, 2H). m/z [M+H]⁺ 419.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-morpholinopyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-morpholinopyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.86 (s, 1H), 8.36 (d, J=8.5 Hz, 1H), 8.10(d, J=5.6 Hz, 1H), 7.82-7.69 (m, 1H), 7.62-7.41 (m, 5H), 6.94 (d, J=8.5Hz, 1H), 6.12 (s, 1H), 3.73 (s, 5H), 1.93-1.80 (m, 1H), 0.99 (d, J=8.4Hz, 2H), 0.68-0.56 (m, 2H). m/z [M+H]⁺ 474.1

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-fluoropyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by substituting 2-fluoropyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.32 (bs, 1H), 8.35 (d, J=8.5 Hz, 1H), 8.17(d, J=5.1 Hz, 1H), 7.83-7.73 (m, 2H), 7.82 (bs, 1H), 7.66-7.49 (m, 3H),6.96 (d, J=8.5 Hz, 1H), 6.13 (s, 1H), 1.92-1.82 (m, 1H), 1.00 (d, J=8.3Hz, 2H), 0.70-0.58 (m, 2H). m/z [M+H]⁺ 407.0

1-(2-Chlorophenyl)-4-((2-chloropyridin-4-yl)amino)-7-cyclopropylquinazolin-2(1H)-onewas prepared by substituting 2-chloropyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.21 (bs, 1H), 8.33 (d, J=6.1 Hz, 2H), 8.16(bs, 1H), 7.91 (bs, 1H), 7.81-7.70 (m, 1H), 7.66-7.41 (m, 3H), 6.95 (d,J=8.5 Hz, 1H), 6.12 (s, 1H), 1.93-1.80 (m, 1H), 0.99 (d, J=8.3 Hz, 2H),0.72-0.54 (m, 2H). m/z [M+H]⁺ 423.0

1-(2-Chlorophenyl)-5-methoxy-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting cyclopropylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.01 (s, 1H), 8.49 (d, J=8.5 Hz, 1H),7.81-7.70 (m, 1H), 7.67-7.54 (m, 4H), 6.44 (s, 1H), 3.50-3.25 (m, 1H),1.28-1.15 (m, 1H), 0.52 (d, J=7.8 Hz, 2H), 0.38-0.29 (m, 2H). m/z [M+H]⁺394.1

(R)-1-(2-Chlorophenyl)-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)amino)quinazolin-2(1H)-onewas prepared by substituting (R)-1,1,1-trifluoropropan-2-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.03-8.92 (m, 1H), 8.66 (t, J=7.3 Hz, 1H),7.83-7.74 (m, 1H), 7.70 (d, J=8.5 Hz, 1H), 7.67-7.53 (m, 3H), 6.49 (s,1H), 5.43 (h, J=7.6 Hz, 1H), 1.53-1.47 (m, 3H), 1.34-1.15 (m, 1H). m/z[M+H]⁺ 436.0

(trans)-3-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)cyclobutane-1-carbonitrilewas prepared by substituting trans-3-aminocyclobutane-1-carbonitrile and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=6.3 Hz, 1H), 8.50 (d, J=8.5 Hz,1H), 7.81-7.74 (m, 1H), 7.70-7.53 (m, 4H), 6.44 (s, 1H), 4.93 (p, J=7.6Hz, 1H), 3.40-3.25 (m, 1H), 2.76-2.58 (m, 4H). m/z [M+H]⁺ 419.05

4-(isopropylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one wasprepared by substituting isopropylamine1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (d, J=5.8 Hz, 1H), 8.43 (d, J=7.8 Hz,1H), 7.68-7.49 (m, 4H), 7.35 (d, J=7.6 Hz, 2H), 6.54 (s, 1H), 4.55-4.45(m, 1H), 1.29 (d, J=6.2 Hz, 6H). m/z [M+H]⁺ 348.1

1-(2-Chlorophenyl)-4-(isopropylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting isopropylamine and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (d, J=8.2 Hz, 2H), 7.81-7.73 (m, 1H),7.66-7.53 (m, 4H), 6.43 (s, 1H), 4.52 (h, J=7.0 Hz, 1H), 1.35-1.25 (m,6H). m/z [M+H]⁺ 382.0

1-(2-Chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting cyclopropylamine and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (s, 1H), 8.44 (d, J=8.5 Hz, 1H),7.81-7.74 (m, 1H), 7.65-7.51 (m, 3H), 6.68 (bs, 1H), 6.43 (s, 1H),3.18-3.08 (m, 1H), 0.85 (d, J=7.4 Hz, 2H), 0.80-0.70 (m, 2H). m/z [M+H]⁺380.0.

1-(2-Chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting isoxazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)-quinazoline-2,4(1H,3H)-dione.

1-(2-Chlorophenyl)-4-((1,3-difluoropropan-2-yl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 1,3-difluoropropan-2-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J=7.5 Hz, 1H), 8.62 (d, J=8.5 Hz,1H), 7.81-7.76 (m, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.65-7.56 (m, 3H), 6.47(s, 1H), 5.06-4.89 (m, 1H), 4.89-4.62 (m, 4H). m/z [M+H]⁺ 418.1

1-(2-Chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1R,2S)-2-fluorocyclopropan-1-amine HCl and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.53 (d, J=8.5 Hz, 1H),7.84-7.75 (m, 1H), 7.69-7.53 (m, 4H), 6.46 (s, 1H), 4.90 (d, J=65.0 Hz,1H), 3.15-3.05 (m, 1H), 1.48-1.17 (m, 2H). m/z [M+H]⁺ 398.05.

1-(2-Chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine HCl and1-(2-chlorophenyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.53 (d, J=8.5 Hz, 1H),7.84-7.75 (m, 1H), 7.69-7.53 (m, 4H), 6.46 (s, 1H), 4.90 (d, J=65.0 Hz,1H), 3.15-3.05 (m, 1H), 1.48-1.17 (m, 2H). m/z [M+H]⁺ 398.1.

4-((Cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting cyclopropylmethanamine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.91 (s, 1H), 8.44 (d, J=8.9 Hz, 1H),7.66-7.49 (m, 3H), 7.35 (d, J=7.6 Hz, 2H), 6.90 (bs, 1H), 6.55 (s, 1H),3.38-3.26 (m, 2H), 1.31-1.16 (m, 1H), 0.51 (d, J=7.7 Hz, 2H), 0.36-0.26(m, 2H). m/z [M+H]⁺ 360.1

7-isopropyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one was prepared bysubstituting 7-isopropyl-1-phenylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (s, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.58(t, J=7.0 Hz, 2H), 7.51 (d, J=6.6 Hz, 1H), 7.26 (d, J=7.6 Hz, 2H), 7.11(d, J=8.4 Hz, 1H), 6.20 (s, 1H), 2.97 (s, 3H), 2.73 (p, J=7.1 Hz, 1H),1.04 (d, J=6.6 Hz, 6H). m/z [M+H]⁺ 294.2.

4-((2,2-Difluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 2,2-difluorocyclopropan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (s, 1H), 7.65-7.59 (m, 3H), 7.56 (t,J=7.7 Hz, 2H), 7.35 (t, J=7.6 Hz, 2H), 6.57 (d, J=8.9 Hz, 1H), 6.18-5.87(m, 1H), 3.78-3.65 (m, 1H), 2.15-2.06 (m, 1H), 1.94-1.82 (m, 1H). m/z[M+H]⁺ 382.05.

4-((1,3-Difluoropropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 1,3-difluoropropan-2-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.83 (d, J=7.4 Hz, 1H), 8.56 (d, J=8.4 Hz,1H), 7.62 (t, J=6.8 Hz, 3H), 7.56 (d, J=7.5 Hz, 1H), 7.37 (d, J=7.6 Hz,2H), 6.58 (s, 1H), 5.03-4.87 (m, 1H), 4.86-4.75 (m, 2H), 4.76-4.62 (m,2H). m/z [M+H]⁺ 384.1.

(R)-4-((1-Cyclopropylethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (R)-1-cyclopropylethan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=8.0 Hz, 1H), 8.32 (d, J=8.4 Hz,1H), 7.45-7.28 (m, 4H), 7.16 (s, 2H), 6.35 (s, 1H), 3.67 (q, J=7.6 Hz,1H), 2.34-2.27 9m, 1H), 1.13 (d, J=6.4 Hz, 3H), 0.99-0.87 (m, 2H),0.40-0.22 (m, 2H). m/z [M+H]⁺ 374.1.

4-(((1-Fluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1-fluorocyclopropyl)methanamine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=6.2 Hz, 1H), 8.53 (d, J=8.5 Hz,1H), 7.66-7.49 (m, 4H), 7.36 (d, J=7.6 Hz, 2H), 6.57 (s, 1H), 4.02 (dd,J=21.5, 5.4 Hz, 2H), 1.07 (d, J=19.0 Hz, 2H), 0.95 (d, J=8.0 Hz, 2H).m/z [M+H]⁺ 378.1.

4-((((trans)-2-(hydroxymethyl)cyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (trans-2-(aminomethyl)cyclopropyl)methanoland 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (s, 1H), 8.43 (d, J=8.4 Hz, 1H),7.66-7.48 (m, 4H), 7.35 (d, J=7.6 Hz, 2H), 6.55 (s, 1H), 4.53 (s, 1H),3.55-3.41 (m, 2H), 3.36-3.19 (m, 2H), 1.16-1.06 (m, 1H), 1.02-0.92 (m,1H), 0.52-0.35 (m, 2H). m/z [M+H]⁺ 390.1

1-(Imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting(1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.12 (s, 1H), 8.41 (d, J=8.4 Hz, 1H), 7.80(d, J=9.1 Hz, 1H), 7.71-7.65 (m, 2H), 7.60 (s, 1H), 7.46 (t, J=8.1 Hz,1H), 7.18 (d, J=7.1 Hz, 1H), 6.50 (s, 1H), 3.09-3.02 (m, 3H). m/z [M+H]⁺360.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.68 (s, 1H), 8.32 (d, J=8.2 Hz, 1H), 7.60(d, J=5.4 Hz, 1H), 7.48-7.40 (m, 2H), 7.34 (d, J=5.7 Hz, 1H), 7.19 (d,J=8.1 Hz, 1H), 2.99 (d, J=4.3 Hz, 3H), 2.05-1.96 (m, 1H), 0.87-0.79 (m,2H), 0.54-0.47 (m, 2H). m/z [M+H]⁺ 327.1

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (d, J=4.9 Hz, 1H), 8.59 (d, J=7.4 Hz,1H), 8.31 (d, J=8.4 Hz, 1H), 8.01 (s, 1H), 7.62 (s, 1H), 7.43 (s, 1H),7.18 (d, J=8.4 Hz, 1H), 6.76 (d, J=7.3 Hz, 1H), 2.99 (s, 3H), 2.06-1.97(m, 1H), 0.89-0.82 (m, 2H), 0.64-0.56 (m, 2H). m z [M+H]⁺ 333.1

7-Methoxy-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one wasprepared by substituting7-methoxy-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.46 (d, J=4.9 Hz, 1H), 8.35 (d, J=7.6 Hz,1H), 7.48 (t, J=7.7 Hz, 2H), 7.39 (t, J=7.5 Hz, 1H), 7.24 (d, J=7.6 Hz,2H), 6.64 (d, J=8.6 Hz, 1H), 3.48 (s, 3H), 2.97 (d, J=2.7 Hz, 3H). m/z[M+H]⁺ 283.1

1-(3-Chloropyridin-2-yl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting1-(3-chloropyridin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.68 (d, J=4.5 Hz, 1H), 8.40(d, J=8.4 Hz, 1H), 8.30 (d, J=8.0 Hz, 1H), 7.72-7.62 (m, 2H), 6.47 (s,1H), 3.03 (d, J=4.3 Hz, 3H). m z [M+H]⁺ 355.0

4-(Methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by substituting7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.04 (s, 1H), 8.93 (d, J=4.7 Hz, 1H), 8.37(d, J=8.3 Hz, 1H), 8.18 (d, J=8.1 Hz, 1H), 8.01 (t, J=6.3 Hz, 1H), 7.64(d, J=8.3 Hz, 1H), 6.52 (s, 1H), 3.02 (s, 3H). m/z [M+H]⁺ 389.1

4-(Methylamino)-1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting1-(pyrimidin-5-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.34 (s, 1H), 9.01 (s, 1H), 8.94 (s, 2H),8.36 (d, J=8.4 Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 6.80 (s, 1H), 3.03 (s,3H). m/z [M+H]⁺ 322.1.

(S)-1-Phenyl-7-(trifluoromethyl)-4-((1,1,1-trifluoropropan-2-yl)amino)quinazolin-2(1H)-onewas prepared by substituting (S)-1,1,1-trifluoropropan-2-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=8.2 Hz, 1H), 8.59 (d, J=8.1 Hz,1H), 7.68-7.52 (m, 4H), 7.44-7.33 (m, 2H), 6.59 (s, 1H), 5.42 (s, 1H),1.48 (d, J=7.1 Hz, 3H). m z [M+H]⁺ 402.1.

4-((Oxetan-2-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting oxetan-2-ylmethanamine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.96 (s, 1H), 8.46 (d, J=8.4 Hz, 1H),7.67-7.50 (m, 4H), 7.35 (d, J=7.5 Hz, 2H), 6.56 (s, 1H), 5.01 (p, J=6.5Hz, 1H), 4.61-4.44 (m, 2H), 3.92-3.71 (m, 2H), 2.69 (q, J=8.4, 6.8 Hz,1H), 2.52-2.42 (m, 1H). m/z [M+H]⁺ 376.1

4-(((1R,2S)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (1R,2S)-2-fluorocyclopropan-1-amine HCl and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.47 (d, J=8.5 Hz, 1H),7.67-7.49 (m, 4H), 7.37 (s, 2H), 6.57 (s, 1H), 4.89 (d, J=65.1 Hz, 1H),3.13-3.02 (m, 1H), 1.45-1.18 (m, 2H). m/z [M+H]⁺ 364.1

4-(((trans)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (trans)-2-fluorocyclopropan-1-amine HCl and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.31 (d, J=8.0 Hz, 1H),7.69-7.51 (m, 4H), 7.35 (d, J=7.5 Hz, 2H), 6.56 (s, 1H), 4.88 (d, J=63.1Hz, 1H), 3.35-3.23 (m, 1H), 1.61-1.45 (m, 1H), 1.30-1.17 (m, 1H). m/z[M+H]⁺ 364.1.

4-(((2,2-Difluorocyclopropyl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (2,2-difluorocyclopropyl)methanamine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.03 (s, 1H), 8.40 (d, J=8.4 Hz, 1H),7.66-7.50 (m, 4H), 7.35 (d, J=7.6 Hz, 2H), 6.56 (s, 1H), 3.69-3.54 (m,2H), 2.28-2.14 (m, 1H), 1.73-1.58 (m, 1H), 1.48-1.36 (m, 1H). m/z [M+H]⁺396.1.

(R)-4-((1-Hydroxypropan-2-yl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (R)-2-aminopropan-1-ol and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.50 (d, J=8.3 Hz, 1H), 8.34 (d, J=7.7 Hz,1H), 7.64-7.52 (m, 4H), 7.34 (d, J=7.6 Hz, 2H), 6.55 (s, 1H), 4.90 (s,1H), 4.45 (p, J=6.8 Hz, 1H), 3.55 (d, J=40 Hz, 1H), 1.24 (d, J=6.6 Hz,3H). m/z [M+H]⁺ 364.1.

4-(oxetan-3-ylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting oxetan-3-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.24 (s, 1H), 8.50 (d, J=8.5 Hz, 1H), 7.61(t, J=7.5 Hz, 4H), 7.33 (d, J=7.7 Hz, 2H), 6.56 (s, 1H), 5.16 (p, J=6.5Hz, 1H), 4.88 (t, J=7.3 Hz, 2H), 4.70 (t, J=6.4 Hz, 2H). m/z [M+H]⁺362.1.

4-(((trans)-3-methoxycyclobutyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting (trans)-3-methoxycyclobutan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80 (d, J=6.3 Hz, 1H), 8.49 (d, J=8.5 Hz,1H), 7.64-7.53 (m, 4H), 7.34 (d, J=7.6 Hz, 2H), 6.54 (s, 1H), 4.77-4.62(m, 1H), 4.12-4.00 (m, 1H), 3.20 (s, 3H), 2.44-2.31 (m, 4H). m/z [M+H]⁺390.1.

4-((3-Methoxypropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 3-methoxypropan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.76 (s, 1H), 8.39 (d, J=8.4 Hz, 1H),7.64-7.51 (m, 4H), 7.35 (d, J=7.6 Hz, 2H), 6.55 (s, 1H), 3.57 (q, J=6.8Hz, 2H), 3.45 (t, J=6.2 Hz, 2H), 3.28 (s, 3H), 1.91 (p, J=7.1 Hz, 2H).m/z [M+H]⁺ 378.1.

4-((2-Methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 2-methoxyethan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.43 (d, J=8.5 Hz, 1H), 7.64-7.51 (m, 4H),7.35 (d, J=7.6 Hz, 2H), 6.55 (s, 1H), 3.75-3.66 (m, 2H), 3.61 (t, J=5.9Hz, 2H), 3.32 (s, 3H). m/z [M+H]⁺ 364.1.

4-((2-(Difluoromethoxy)ethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 2-(difluoromethoxy)ethan-1-amine and1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.41 (d, J=8.5 Hz, 1H), 7.67-7.51 (m, 4H),7.36 (d, J=7.6 Hz, 2H), 6.84 (d, J=75.8 Hz, 1H), 6.56 (s, 1H), 4.17-4.07(m, 2H), 3.82-3.73 (m, 2H). m/z [M+H]⁺ 400.1.

7-Cyclopropyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by substituting7-cyclopropyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.56 (d, J=5.2 Hz, 1H), 8.29 (d, J=8.1 Hz,1H), 7.49-7.35 (m, 3H), 7.16 (d, J=7.6 Hz, 3H), 2.97 (d, J=4.3 Hz, 3H),1.98 (p, J=6.6 Hz, 1H), 0.82 (d, J=7.7 Hz, 2H), 0.54-0.46 (m, 2H). m/z[M+H]⁺ 293.1

(R)-4-(3-Hydroxypyrrolidin-1-yl)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using (R)-pyrrolidin-3-ol and1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (br s, 1H), 7.61 (d, J=8.1 Hz, 1H),7.49 (m, 2H), 7.41 (m, 2H), 7.24 (d, J=7.6 Hz, 2H), 4.45 (s, 1H), 3.74(m, 4H), 2.03 (t, J=11.5 Hz, 2H).

1-(2-Bromophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-bromophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 9.13 (br s, 1H), 8.81 (d, J=8.1 Hz, 1H), 7.80(t, J=7.4 Hz, 2H), 7.53 (t, J=7.7 Hz, 1H), 7.48-7.33 (m, 2H), 3.04 (s,3H). m/z [M+H]⁺ 401.0, 399.0.

1-(2-Fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 9.13 (s, 1H), 8.79 (d, J=8.1 Hz, 1H), 7.82 (d,J=8.1 Hz, 1H), 7.49 (m, 1H), 7.46-7.27 (m, 3H), 3.03 (s, 3H). m/z [M+H]⁺339.1

1-(2-chlorophenyl)-4-(pyridin-3-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using pyridin-3-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 9.19 (d, J=8.2 Hz, 1H), 9.03 (s,1H), 8.45 (d, J=4.6 Hz, 1H), 8.34 (d, J=8.4 Hz, 1H), 7.95 (d, J=8.0 Hz,1H), 7.73-7.62 (m, 1H), 7.52 (d, J=7.9 Hz, 4H). m/z [M+H]⁺ 418.0.

1-(2-Chlorophenyl)-4-((1-methyl-1H-pyrazol-5-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 1-methyl-1H-pyrazol-5-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 10.80 (s, 1H), 9.05 (d, J=8.2 Hz, 1H), 8.33 (s,1H), 7.88 (d, J=8.1 Hz, 1H), 7.79 (s, 1H), 7.66 (m, 1H), 7.50 (m, 3H),3.90 (s, 3H). m/z [M+H]⁺ 421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-imidazol-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 1-methyl-1H-imidazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.82 (d, J=7.7 Hz, 1H), 8.01 (s, 1H), 7.75 (d,J=8.0 Hz, 1H), 7.68 (d, J=6.4 Hz, 1H), 7.63-7.57 (m, 1H), 7.53 (dd,J=5.9, 3.2 Hz, 3H), 7.44 (s, 1H), 3.76 (s, 3H). m/z [M+H]⁺ 421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-3-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 1-methyl-1H-pyrazol-3-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 10.62 (s, 1H), 8.96 (s, 1H), 7.82 (s, 1H), 7.68(s, 1H), 7.50 (d, J=27.4 Hz, 4H), 6.32 (s, 1H), 3.77 (s, 3H). m/z [M+H]⁺421.0.

1-(2-chlorophenyl)-4-((1-methyl-1H-pyrazol-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 1-methyl-1H-pyrazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 11.95 (s, 1H), 8.83 (d, J=8.0 Hz, 1H), 7.81 (s,1H), 7.76 (d, J=8.2 Hz, 1H), 7.72-7.67 (m, 1H), 7.64-7.58 (m, 1H),7.57-7.47 (m, 3H), 6.36 (s, 1H), 3.94 (s, 3H). m/z [M+H]⁺ 421.0.

1-(2-chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using isoxazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 11.09 (br s, 1H), 9.50 (s, 1H), 9.02 (d, J=8.2Hz, 1H), 8.94 (s, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.68 (d, J=6.1 Hz, 1H),7.58-7.44 (m, 3H). m/z [M+H]⁺ 408.0

1-(2-Chlorophenyl)-4-((5-methylisoxazol-3-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using isoxazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.98 (d, J=8.1 Hz, 1H), 7.72 (d, J=8.1 Hz, 1H),7.68-7.58 (m, 1H), 7.53 (s, 4H), 6.25 (s, 1H), 2.48 (s, 3H). m/z [M+H]⁺422.05.

1-(2-Chlorophenyl)-4-((2-methylpyridin-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 2-methylpyridin-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.73 (d, J=8.3 Hz, 1H), 7.91 (br s, 1H), 7.72(d, J=8.1, 1H), 7.66 (d, J=7.3 Hz, 1H), 7.60-7.38 (m, 3H), 6.70 (br s,1H), 6.65 (s, 1H), 2.47 (s, 3H).

1-(2-Chlorophenyl)-4-((2-methoxypyridin-4-yl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 2-methoxypyridin-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

1-(2-Chlorophenyl)-7-(trifluoromethyl)-4-((2-(trifluoromethyl)pyridin-4-yl)amino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using 2-(trifluoromethyl)pyridin-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 9.07 (br s, 1H), 8.72 (br s, 1H), 8.49 (br s,1H), 7.82 (br s, 1H), 7.65 (br s, 1H), 7.59-7.42 (m, 4H). m/z [M+H]⁺486.05.

1-(2-chlorophenyl)-4-(isothiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using isothiazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 9.63 (s, 1H), 9.00 (d, J=8.4 Hz, 1H), 8.93 (s,1H), 7.79 (d, J=8.4 Hz, 1H), 7.72-7.61 (m, 1H), 7.59-7.38 (m, 3H). m/z[M+H]⁺ 424.0.

7-ethyl-4-(methylamino)-1-phenylpyrido[2,3-d]pyrimidin-2(1H)-one wasprepared by using7-ethyl-1-phenylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.61 (br, 1H), 8.37 (d, J=8.2, 1H), 7.52-7.42(m, 2H), 7.41-7.33 (m, 1H), 7.20 (d, J=7.7 Hz, 2H), 7.13 (d, J=8.0, 1H),2.98 (d, J=4.5, 3H), 2.56 (q, J=7.6 Hz, 2H), 1.00 (t, J=7.5 Hz, 3H). m/z[M+H]⁺ 281.2.

7-Ethyl-4-(methylamino)-1-(o-tolyl)pyrido[2,3-d]pyrimidin-2(1H)-one wasprepared by using7-ethyl-1-(o-tolyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.63 (br s, 1H), 8.39 (d, J=8.6 Hz, 1H), 7.30(m, 3H), 7.11 (m, 2H), 3.04-2.94 (s, 3H), 2.55 (q, J=7.7 Hz, 2H), 1.90(s, 3H), 0.98 (t, J=7.6, 3H). m/z [M+H]⁺ 295.15.

1-(2-Chlorophenyl)-7-ethyl-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.72 (br s, 1H), 8.40 (d, J=8.2 Hz, 1H), 7.61(br s, 1H), 7.50-7.41 (m, 2H), 7.37 (br s, 1H), 7.16 (d, J=8.2 Hz, 1H),2.99 (s, 3H), 2.58 (q, J=7.6 Hz, 2H), 0.99 (t, J=7.6 Hz, 3H). m/z [M+H]⁺315.1.

7-ethyl-1-(2-fluorophenyl)-4-(methylamino)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-fluorophenyl)-7-ethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.0, 1H), 7.50 (m, 1H), 7.32 (m, 8.3Hz, 2H), 7.17 (d, J=8.3, 1H), 3.14 (s, 3H), 2.79-2.59 (q, J=7.6 Hz, 2H),1.33 (d, J=6.6 Hz, 1H), 1.10 (t, J=7.6 Hz, 3H). m/z [M+H]⁺ 299.1.

7-Ethyl-4-(methylamino)-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using7-ethyl-1-(pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.60 (br s, 1H), 8.51 (s, 1H), 8.30 (d, J=8.2Hz, 1H), 7.85 (d, J=8.3 Hz, 1H), 7.64 (m, 1H), 7.19 (d, J=8.2 Hz, 1H),3.15 (s, 3H), 2.70 (q, J=7.3 Hz, 2H), 1.33 (d, J=6.6 Hz, 1H), 1.10 (dd,J=8.5, 6.7 Hz, 3H). m/z [M+H]⁺ 282.15.

1-(2-chlorophenyl)-4-(cyclopropylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using cyclopropylamine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.21 (d, J=8.7 Hz, 1H), 7.75 (m, 1H), 7.61 (m,2H), 7.55-7.36 (m, 1H), 7.17 (d, J=9.0 Hz, 1H), 6.24 (s, 1H), 3.17 (m,1H), 0.95 (d, J=7.2 Hz, 2H), 0.80 (m, 2H). m/z [M+H]⁺ 396.0

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using cyclopropylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.28 (d, J=8.8 Hz, 1H), 7.74 (m, 1H), 7.60 (m,2H), 7.48 (m, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.25 (s, 1H), 3.53 (m, 2H),1.40-1.19 (m, 1H), 0.60 (d, J=7.7 Hz, 2H), 0.39 (m, 2H). m/z [M+H]⁺410.0

1-(2-chlorophenyl)-4-((2-methoxyethyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using 2-methoxyethan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.25 (d, J=9.1 Hz, 1H), 7.74 (m, 1H), 7.67-7.57(m, 2H), 7.49 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 6.25 (s, 1H), 3.85 (m,2H), 3.72 (m, 2H), 3.43 (s, 2H). m/z [M+H]⁺ 414.0.

1-(2-Chlorophenyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using trans-3-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.35 (d, J=8.8 Hz, 1H), 7.81-7.66 (m, 1H),7.65-7.53 (m, 2H), 7.47 (m, 1H), 7.20 (d, J=9.0 Hz, 1H), 6.24 (s, 1H),4.53 (m, 1H), 2.63-2.40 (m, 4H). m/z [M+H]⁺ 426.1.

1-(2-Chlorophenyl)-4-((2-hydroxyethyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using 2-aminoethan-1-ol and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.30 (d, J=9.0, Hz, 1H), 7.75 (m, 1H),7.69-7.58 (m, 2H), 7.51 (m, 1H), 7.25 (d, J=9.0 Hz, 1H), 6.28 (s, 1H),3.92-3.86 (m, 2H), 3.86-3.76 (m, 2H). m/z [M+H]⁺ 400.1.

1-(2-Chlorophenyl)-4-(((1R,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using (1R,2S)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.38 (d, J=9.0 Hz, 1H), 7.75 (m,1H), 7.69-7.49 (m, 3H), 7.25 (d, J=8.8 Hz, 1H), 6.11 (s, 1H), 4.86 (d,J=64.6 Hz, 1H), 3.06 (br s, 1H), 1.38-1.24 (m, 1H), 1.19 (d, J=6.4 Hz,1H). m/z [M+H]⁺ 414.05

1-(2-Chlorophenyl)-4-(((1S,2R)-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using (1S,2R)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.79 (s, 1H), 8.38 (d, J=9.0 Hz, 1H), 7.75 (m,1H), 7.69-7.49 (m, 3H), 7.25 (d, J=8.8 Hz, 1H), 6.11 (s, 1H), 4.86 (d,J=64.6 Hz, 1H), 3.06 (br s, 1H), 1.38-1.24 (m, 1H), 1.19 (d, J=6.4 Hz,1H). m/z [M+H]⁺ 414.05.

1-(2-Chlorophenyl)-4-(isoxazol-4-ylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using isoxazol-4-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 9.46 (s, 1H), 8.90 (s, 1H), 8.50 (d, J=8.5 Hz,1H), 7.78 (m, 1H), 7.61 (m, 3H), 7.39 (d, J=8.9 Hz, 1H), 6.18 (s, 1H).m/z [M+H]⁺ 423.0.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using trans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.31 (d, J=9.0, 2.1 Hz, 1H), 7.74 (m, 1H),7.67-7.54 (m, 2H), 7.48 (m, 1H), 7.21 (d, J=9.0 Hz, 1H), 6.25 (s, 1H),4.23 (m, 1H), 2.24 (m, 2H), 1.68 (m, 2H). m/z [M+H]⁺ 426.1.

4-Amino-1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one wasprepared by using ammonia in THF (2 M) and1-(2-chlorophenyl)-7-(trifluoromethoxy)-quinazoline-2,4(1H,3H)-dione

1-(2-Chlorophenyl)-4-(cyclopropylamino)-7-(1,1-difluoroethyl)quinazolin-2(1H)-onewas prepared by using cyclopropanamine and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.19 (d, J=8.5 Hz, 1H), 7.74 (m, 1H), 7.60 (m,1H), 7.49 (m, 1H), 7.41 (d, J=8.5 Hz, 1H), 6.56 (s, 1H), 3.17 (br s,1H), 1.82 (t, J=18.4 Hz, 2H), 1.31 (d, J=6.4 Hz, 1H), 0.95 (d, J=7.2 Hz,1H), 0.81 (m, 1H). m/z [M+H]⁺ 376.1.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-hydroxyethyl)amino)quinazolin-2(1H)-onewas prepared by using 2-aminoethan-1-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.22 (d, J=8.5 Hz, 1H), 7.73 (m, 1H), 7.60 (m,2H), 7.46 (m, 2H), 6.56 (s, 1H), 3.97-3.72 (m, 4H), 1.83 (t, J=18.1,3H). m/z [M+H]⁺ 380.05.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-((2-methoxyethyl)amino)quinazolin-2(1H)-onewas prepared by using 2-methoxyethan-1-amine and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.22 (d, J=8.4 Hz, 1H), 7.84-7.69 (m, 1H), 7.60(m, 2H), 7.46 (m, 2H), 6.56 (s, 1H), 3.94-3.80 (m, 2H), 3.73 (m, 2H),3.43 (s, 3H), 1.83 (t, J=18.4, 3H). m/z [M+H]⁺ 394.05.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-3-hydroxycyclobutyl)amino)-quinazolin-2(1H)-onewas prepared by using trans-3-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione

¹H NMR (400 MHz, MeOD) δ 8.32 (d, J=8.5 Hz, 1H), 7.73 (m, 1H), 7.60 (m,2H), 7.46 (m, 2H), 6.56 (s, 1H), 4.59-4.45 (m, 1H), 2.63-2.44 (m, 4H),1.83 (t, J=18.4, 3H). m/z [M+H]⁺ 406.1.

7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.20 (d, J=7.5 Hz, 1H), 7.84 (d, J=9.0 Hz, 1H),7.70-7.56 (m, 3H), 7.50 (d, J=8.5 Hz, 1H), 7.23 (d, J=7.1 Hz, 1H), 6.58(s, 1H), 3.20 (s, 3H), 1.78 (t, J=18.5, 3H). m/z [M+H]⁺ 356.1.

4-(Cyclopropylamino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylamine and7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.29 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.3 Hz, 1H),7.88 (m, 3H), 7.50 (t, J=8.5 Hz, 2H), 6.71 (s, 1H), 3.23 (m, 1H), 1.80(t, J=18.5, 3H), 0.98 (d, J=7.4 Hz, 2H), 0.86 (m, 2H). m/z [M+H]⁺ 382.2.

4-((Cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.35 (d, J=8.4 Hz, 1H), 8.00 (d, J=9.2 Hz, 1H),7.92-7.79 (m, 3H), 7.54 (d, J=8.6 Hz, 1H), 7.48 (d, J=7.2 Hz, 1H), 6.71(s, 1H), 3.68-3.48 (m, 2H), 1.81 (t, J=18.5, 3H), 1.33 (m, 1H), 0.62 (d,J=7.7 Hz, 2H), 0.42 (m, 2H). m/z [M+H]⁺ 396.2.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)quinazolin-2(1H)-onewas prepared by using cyclopropylamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.95 (d, J=8.5 Hz, 1H), 7.72 (m, 1H), 7.58 (m,2H), 7.44 (m, 1H), 6.92 (d, J=8.4 Hz, 1H), 6.15 (s, 1H), 3.12 (m, 1H),1.83 (m, 1H), 1.01 (d, J=8.2 Hz, 2H), 0.93 (d, J=7.0 Hz, 2H), 0.78 (m,2H), 0.61 (m, 2H). m/z [M+H]⁺ 352.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.80 (d, J=8.2 Hz, 1H), 7.50 (m, 1H), 7.37 (m,2H), 7.22 (m, 1H), 6.74 (d, J=8.5 Hz, 1H), 5.94 (s, 1H), 3.30 (m, 2H),2.61 (m, 2H), 1.63 (m, 1H), 1.16-0.98 (m, 2H), 0.80 (d, J=8.2 Hz, 2H),0.43-0.32 (m, 2H), 0.17 (d, J=4.5 Hz, 2H). m/z [M+H]⁺ 366.1.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxyethyl)amino)quinazolin-2(1H)-onewas prepared by using 2-aminoethan-1-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.97 (d, J=8.5 Hz, 1H), 7.71 (m, 1H), 7.58 (m,2H), 7.51-7.36 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.15 (s, 1H), 3.84 (m,2H), 3.78 (m, 2H), 1.83 (br s, 1H), 1.01 (d, J=8.2 Hz, 2H), 0.62 (br s,2H). m/z [M+H]⁺ 356.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-methoxyethyl)amino)quinazolin-2(1H)-onewas prepared by using 2-methoxyethan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.97 (d, J=8.7 Hz, 1H), 7.72 (m, 1H), 7.58 (m,2H), 7.44 (m, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.15 (s, 1H), 3.93-3.76 (m,2H), 3.71 (m, 2H), 3.42 (s, 3H), 1.84 (m, 1H), 1.01 (d, J=7.9 Hz, 2H),0.62 (br s, 2H). m/z [M+H]⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-onewas prepared by using trans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.04 (d, J=8.5 Hz, 1H), 7.81-7.66 (m, 1H), 7.58(m, 2H), 7.43 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.15 (s, 1H), 4.21 (s,1H), 2.23 (m, 2H), 1.84 (m, 1H), 1.68 (m, 2H), 1.02 (d, J=8.3 Hz, 2H),0.62 (d, J=4.8 Hz, 2H). m/z [M+H]⁺ 382.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-methylcyclobutyl)amino)quinazolin-2(1H)-onewas prepared by using 1-methylcyclobutan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.99 (d, J=9.1 Hz, 1H), 7.71 (m, 1H), 7.57 (m,2H), 7.48-7.26 (m, 1H), 6.92 (d, J=8.2 Hz, 1H), 6.12 (s, 1H), 2.46 (m,2H), 2.31 (m, 2H), 1.94 (m, 2H), 1.83 (m, 1H), 1.72 (s, 3H), 1.00 (d,J=8.1 Hz, 2H), 0.67-0.45 (m, 2H). m/z [M+H]⁺ 380.15.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((R)-1-hydroxypropan-2-yl)amino)quinazolin-2(1H)-onewas prepared by using (R)-2-aminopropan-1-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.05 (d, J=8.4, 1H), 7.72 (m, 1H), 7.57 (m,2H), 7.43 (m, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 4.77-4.53 (m,1H), 3.71 (m, 2H), 1.82 (m, 1H), 1.35 (d, J=6.3 Hz, 3H), 1.01 (d, J=8.1Hz, 2H), 0.62 (s, 2H). m/z [M+H]⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((S)-1-hydroxypropan-2-yl)amino)quinazolin-2(1H)-onewas prepared by using (S)-2-aminopropan-1-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.05 (d, J=8.4, 1H), 7.72 (m, 1H), 7.57 (m,2H), 7.43 (m, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 4.77-4.53 (m,1H), 3.71 (m, 2H), 1.82 (m, 1H), 1.35 (d, J=6.3 Hz, 3H), 1.01 (d, J=8.1Hz, 2H), 0.62 (s, 2H). m/z [M+H]⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-hydroxypropyl)amino)quinazolin-2(1H)-onewas prepared by using 3-aminopropan-1-ol and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.95 (d, J=5.9, 1H), 7.71 (m, 1H), 7.58 (m,2H), 7.44 (m, 1H), 6.95 (d, J=8.5 Hz, 1H), 6.15 (s, 1H), 3.72 (m, 4H),1.96 (t, J=6.7 Hz, 2H), 1.83 (s, 1H), 1.01 (d, J=8.2 Hz, 2H), 0.71-0.49(m, 2H). m/z [M+H]⁺ 370.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methoxypropyl)amino)quinazolin-2(1H)-onewas prepared by using 3-methoxypropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.91 (d, J=8.5, 1H), 7.71 (br s, 1H), 7.58 (brs, 2H), 7.43 (br s, 1H), 6.94 (d, J=8.5 Hz, 1H), 6.15 (s, 1H), 3.72 (t,J=7.2 Hz, 2H), 3.55 (t, J=6.1, 2H), 3.38 (s, 3H), 2.02 (quin, J=5.9 Hz,2H), 1.84 (d, J=7.8 Hz, 1H), 1.01 (br s, 2H), 0.61 (dq, J=4.8, 2.5 Hz,2H). m/z [M+H]⁺ 384.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)(methyl)amino)quinazolin-2(1H)-onewas prepared by using 1-cyclopropyl-N-methylmethanamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 9.24 (s, 1H), 8.17 (d, J=6.1 Hz, 1H), 7.74 (m,1H), 7.60 (m, 1H), 7.47 (m, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.24 (s, 1H),2.44 (s, 2H), 1.88 (m, 1H), 1.05 (d, J=8.4 Hz, 1H), 0.67 (m, 1H). m/z[M+H]⁺ 380.15.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((5-methylisoxazol-4-yl)amino)quinazolin-2(1H)-onewas prepared by using 5-methylisoxazol-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 9.24 (s, 1H), 8.29-8.09 (m, 1H), 7.74 (d, J=5.0Hz, 1H), 7.70-7.57 (m, 2H), 7.47 (d, J=6.3 Hz, 1H), 7.04 (d, J=8.6 Hz,1H), 6.24 (s, 1H), 2.44 (s, 3H), 1.88 (br s, 1H), 1.05 (d, J=8.4 Hz,2H), 0.67 (br s, 2H). m/z [M+H]⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3-methylisoxazol-4-yl)amino)quinazolin-2(1H)-onewas prepared by using 3-methylisoxazol-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.7 (s, 1H), 8.13 (d, J=8.8 Hz, 1H), 7.73 (d,J=7.5 Hz, 1H), 7.59 (d, J=6.5 Hz, 3H), 7.46 (br s, 1H), 7.03 (d, J=8.4Hz, 1H), 6.22 (s, 1H), 2.50 (s, 3H), 1.87 (br s, 1H), 1.05 (d, J=8.8 Hz,2H), 0.65 (br s, 2H). m/z [M+H]⁺ 393.1.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((3,5-dimethylisoxazol-4-yl)amino)quinazolin-2(1H)-onewas prepared by using 3,5-dimethylisoxazol-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

1H NMR (400 MHz, MeOD) δ 8.12 (d, J=8.7 Hz, 1H), 7.72 (br s, 1H), 7.59(m, 2H), 7.46 (br s, 1H), 7.04 (d, J=8.6 Hz, 1H), 6.23 (s, 1H), 2.41 (s,3H), 2.26 (s, 3H), 1.88 (s, 1H), 1.05 (m, 2H), 0.75-0.50 (m, 2H). m/z[M+H]⁺ 407.1.

4-(Methylamino)-1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-(pyrazin-2-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.86 (s, 1H), 8.81 (d, J=7.2 Hz, 2H), 8.25 (d,J=8.5 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 6.84 (s, 1H), 3.18 (d, J=1.9 Hz,3H). m/z [M+H]⁺ 322.1.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(imidazo[1,2-a]pyridin-5-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethanamine and7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

1H NMR (400 MHz, MeOD) δ 8.11 (m, 3H), 8.03 (s, 2H), 7.65 (d, J=5.6 Hz,1H), 6.99 (d, J=8.5 Hz, 1H), 6.47 (s, 1H), 3.55 (m, 2H), 1.86 (s, 1H),1.44-1.26 (m, 1H), 1.00 (d, J=8.1 Hz, 2H), 0.70 (d, J=5.9 Hz, 2H), 0.61(d, J=7.9 Hz, 2H), 0.39 (m, 2H). m/z [M+H]⁺ 372.15.

4-(Methylamino)-1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-(pyridazin-3-yl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 9.40 (s, 1H), 9.05 (br s, 1H), 8.38 (d, J=8.5Hz, 1H), 8.02 (t, J=6.6 Hz, 1H), 7.95 (d, J=8.6 Hz, 1H), 7.65 (d, J=8.4Hz, 1H), 6.64 (s, 1H), 3.04 (s, 3H). m/z [M+H]⁺ 322.1.

7-Cyclopropyl-4-(isoxazol-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-one wasprepared by using isoxazol-4-amine and7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 10.42 (br s, 1H), 9.47 (s, 1H), 8.88 (s, 1H),8.20 (d, J=8.4 Hz, 1H), 7.54-7.36 (m, 3H), 7.22 (d, J=7.2 Hz, 1H), 6.95(d, J=8.5 Hz, 1H), 6.09 (s, 1H), 1.96 (s, 3H), 1.82 (br s, 1H), 0.97 (d,J=8.4 Hz, 2H), 0.61 (br s, 2H). m/z [M+H]⁺ 359.1.

7-Cyclopropyl-4-(isothiazol-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using thioisoxazol-4-amine and7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 10.56 (s, 1H), 9.37 (s, 1H), 8.95 (s, 1H), 8.29(s, 1H), 7.57-7.32 (m, 3H), 7.22 (d, J=7.3 Hz, 1H), 6.95 (d, J=8.4 Hz,1H), 6.10 (s, 1H), 1.96 (s, 3H), 1.83 (br s, 1H), 0.97 (d, J=8.3 Hz,2H), 0.62 (br s, 2H). m/z [M+H]⁺ 375.1.

1-(Imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.99 (br s, 1H), 8.32 (d, J=9.5 Hz, 1H), 7.83(d, J=9.1 Hz, 1H), 7.75 (s, 1H), 7.67 (s, 1H), 7.53 (t, J=8.2 Hz, 1H),7.32 (d, J=8.9 Hz, 1H), 7.22 (d, J=7.2 Hz, 1H), 6.31 (s, 1H), 3.04 (m,3H). m/z [M+H]⁺ 376.1.

4-((Cyclopropylmethyl)amino)-1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)-quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and1-(imidazo[1,2-a]pyridin-5-yl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 9.03 (br s, 1H), 8.43 (d, J=9.0 Hz, 1H), 7.78(d, J=9.0 Hz, 1H), 7.67 (s, 1H), 7.59 (s, 1H), 7.46 (t, J=9.0 Hz, 1H),7.32 (d, J=8.9 Hz, 1H), 7.16 (d, J=7.1 Hz, 1H), 6.23 (s, 1H), 1.24(quin, J=6.7 Hz, 1H), 0.53 (d, J=7.9 Hz, 2H), 0.34 (br s, 2H). m/z[M+H]⁺ 416.1.

7-Cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(2-(difluoromethoxy)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.57 (br s, 1H), 8.41 (s, 1H), 7.99 (d, J=8.2Hz, 2H), 7.83 (s, 1H), 7.50 (m, 1H), 6.85 (d, J=8.4 Hz, 1H), 6.16 (s,1H), 2.98 (s, 3H), 1.87 (m, 1H), 0.95 (d, J=8.7 Hz, 2H), 0.63 (m, 2H).m/z [M+H]⁺ 359.1.

7-Cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.90 (s, 1H), 8.60 (s, 1H), 8.08 (d, J=8.1 Hz,1H), 7.99 (m, 2H), 6.83 (d, J=8.4 Hz, 1H), 6.06 (s, 1H), 3.04-2.93 (m,3H), 1.87 (m, 1H), 0.94 (d, J=8.2 Hz, 2H), 0.61 (m, 2H). m/z [M+H]⁺361.1.

4-Amino-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using ammonia in THF (2 M) and7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.90 (s 1H), 8.10-7.88 (m, 3H), 6.96 (d, J=8.5Hz, 1H), 6.11 (s, 1H), 1.96-1.72 (m, 1H), 1.03 (dd, J=3.4 Hz, 2H), 0.65(d, J=3.9 Hz, 2H). m/z [M+H]⁺ 347.0.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.82 (br s, 1H), 8.47 (s, 1H), 7.75 (m, 1H),7.58 (m, 2H), 7.52 (d, J=4.6 Hz, 1H), 6.53 (s, 1H), 3.06-2.90 (s, 3H).m/z [M+H]⁺ 399.9.

7-Bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and7-bromo-6-chloro-1-(2-chlorophenyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.16 (s, 1H), 7.81 (d, J=7.2 Hz, 2H), 7.73-7.56(m, 3H), 6.61 (s, 1H), 2.67 (br s, 1H), 1.26 (m, 4H). m/z [M+H]⁺ 439.9.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)-onewas prepared by substituting with isoxazol-4-amine and6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 9.67 (s, 1H), 8.79 (s, 1H), 8.58 (s, 1H), 7.76(m, 1H), 7.62 (m, 2H), 7.49 (m, 1H), 6.04 (s, 1H), 2.22 (br s, 1H), 1.06(d, J=8.1 Hz, 2H), 0.39 (br s, 2H). m/z [M+H]⁺ 458.0.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.74 (br s, 1H), 8.56 (s, 1H), 7.81-7.67 (m,1H), 7.66-7.54 (m, 2H), 7.53-7.34 (m, 1H), 5.75 (s, 1H), 2.08 (s, 1H),1.19 (s, 1H), 0.98 (d, J=8.3 Hz, 2H), 0.51 (d, J=7.7 Hz, 2H), 0.35-0.22(m, 4H). m/z [M+H]⁺ 445.0.

4-Amino-6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazolin-2(1H)-onewas prepared by using ammonia in THF (2 M) and6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.21 (s, 1H), 7.72 (m, 1H), 7.65-7.53 (m, 2H),7.44 (m, 1H), 5.97 (s, 1H), 2.23 (m, 1H), 1.13-0.96 (m, 2H), 0.39 (m,2H). m/z [M+H]⁺ 347.0.

(R)-6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)amino)quinazolin-2(1H)-onewas prepared by using (R)-2-aminopropan-1-ol and6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

(S)-6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((2-hydroxypropyl)amino)quinazolin-2(1H)-onewas prepared by using (S)-2-aminopropan-1-ol and6-chloro-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

5-fluoro-4-(((trans)-2-fluorocyclopropyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using trans-2-fluorocyclopropan-1-amine and5-fluoro-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 7.86 (d, J=12.2 Hz, 1H), 7.70-7.53 (m, 3H),7.38 (br s, 2H), 6.39 (s, 1H), 4.92 (d, J=64.9 Hz, 1H), 3.08 (br s, 1H),1.40 (br d, J=25.4 Hz, 1H), 1.27 (m, 1H). m/z [M+H]⁺ 382.1.

4-((Cyclopropylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.70 (m, 1H), 7.56 (dt, J=30.6, 7.5 Hz, 3H),7.31 (d, J=7.6 Hz, 2H), 7.09 (s, 1H), 6.81 (s, 1H), 6.14 (s, 1H), 4.13(s, 3H), 1.26 (s, 1H), 0.50 (d, J=7.8 Hz, 2H), 0.35 (d, J=4.9 Hz, 2H).m/z [M+H]⁺ 390.1.

4-((2-Hydroxyethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using 2-aminoethan-1-ol and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.67 (s, 1H), 7.56 (m, 2H), 7.31 (d, J=7.5 Hz,1H), 7.10 (s, 1H), 6.14 (s, 1H), 4.11 (d, J=2.2 Hz, 3H), 3.71 (t, J=6.2Hz, 1H), 3.60 (t, J=6.1 Hz, 1H). m/z [M+H]⁺ 380.1.

5-Methoxy-4-((2-methoxyethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using 2-methoxyethan-1-amine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

(S)-4-((2-Hydroxypropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (S)-2-aminopropan-1-ol and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO) δ 8.72 (m, 1H), 7.68-7.45 (m, 3H), 7.31 (d, J=7.5Hz, 2H), 7.11 (s, 1H), 6.15 (s, 1H), 5.12 (br s, 1H), 4.11 (s, 3H),4.03-3.90 (br s, 1H), 3.64 (dd, J=12.6, 6.0 Hz, 1H), 1.16 (d, J=6.3,3H). m/z [M+H]⁺ 394.1.

4-(((trans)-2-Hydroxycyclobutyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-cyclopropylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dioneand1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

4-(((trans)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using trans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.57 (s, 1H), 7.76-7.51 (m, 3H), 7.33 (d, J=7.5Hz, 2H), 7.10 (s, 1H), 6.37 (s, 1H), 4.62 (m, 1H), 4.14 (s, 3H), 3.53(m, 1H), 1.55 (m, 1H), 1.22 (m, 1H). m/z [M+H]⁺ 394.05.

4-Amino-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one wasprepared by using ammonia in THF (2 M) and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.61 (m, 4H), 7.33 (d, J=7.6 Hz, 2H), 7.11 (s,1H), 6.36 (s, 1H), 4.62 (br s, 1H), 4.16 (s, 3H). m/z [M+H]⁺ 336.0.

4-(((1S,2R)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (1S,2R)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.71-7.54 (m, 3H), 7.35 (d, J=7.4 Hz, 2H), 7.13(s, 1H), 6.39 (s, 1H), 4.28-4.18 (m, 1H), 4.15 (s, 3H), 4.06 (br s, 1H),3.90 (appar q, J=6.5 Hz, 1H), 1.34 (m, 1H), 1.14 (br d, J=26.1 Hz, 1H).m/z [M+H]⁺ 394.05.

4-(((1R,2S)-2-Fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (1R,2S)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.71-7.54 (m, 3H), 7.35 (d, J=7.4 Hz, 2H), 7.13(s, 1H), 6.39 (s, 1H), 4.28-4.18 (m, 1H), 4.15 (s, 3H), 4.06 (br s, 1H),3.90 (appar q, J=6.5 Hz, 1H), 1.34 (m, 1H), 1.14 (br d, J=26.1 Hz, 1H).m/z [M+H]⁺ 394.05.

4-(Isobutylamino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using sec-Butylamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.72-7.53 (m, 3H), 7.32 (d, J=7.6 Hz, 2H), 7.12(s, 1H), 6.36 (s, 1H), 4.18 (s, 3H), 3.53 (d, J=7.1, 2H), 2.13 (appar q,J=7.2 Hz, 1H), 1.06 (d, J=6.9, 8H). m/z [M+H]⁺ 392.15.

5-Methoxy-4-((oxazol-2-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using oxazol-2-ylmethanamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.92 (s, 1H), 7.71-7.52 (m, 3H), 7.38-7.24 (d,J=7.8 Hz, 2H), 7.16 (d, J=8.6 Hz, 2H), 6.38 (s, 1H), 5.03 (s, 2H), 4.20(s, 3H). m/z [M+H]⁺ 417.1.

4-((Isoxazol-4-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using isoxazol-4-ylmethanamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.82 (s, 1H), 8.62 (s, 1H), 7.76-7.52 (m, 3H),7.34 (d, J=7.6 Hz, 2H), 7.11 (s, 1H), 6.36 (s, 1H), 4.74 (s, 2H), 4.17(s, 3H). m/z [M+H]⁺ 417.1.

5-Methoxy-4-((oxazol-4-ylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using oxazol-4-ylmethanamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.22 (s, 1H), 8.05 (s, 1H), 7.71-7.54 (m, 3H),7.33 (d, J=7.6 Hz, 2H), 7.12 (s, 1H), 6.36 (s, 1H), 4.80 (s, 2H), 4.17(1, 3H). m/z [M+H]⁺ 417.1.

5-Methoxy-4-(((3-methoxyisoxazol-5-yl)methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (3-methoxyisoxazol-5-yl)methanamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 7.74-7.51 (m, 3H), 7.33 (d, J=7.6 Hz, 2H), 7.13(s, 1H), 6.37 (s, 1H), 6.13 (s, 1H), 4.93 (s, 3H), 4.19 (s, 3H), 3.93(s, 3H). m/z [M+H]⁺ 447.1.

4-((isoxazol-3-ylmethyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using isoxazol-3-ylmethanamine and1-(2-chlorophenyl)-5-methoxy-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.73-7.53 (m, 3H), 7.34 (d, J=7.6Hz, 2H), 7.14 (s, 1H), 6.64 (s, 1H), 6.38 (s, 1H), 5.00 (s, 2H), 4.19(d, J=2.5 Hz, 3H). m/z [M+H]⁺ 417.1.

7-cyclopropyl-4-((cyclopropylmethyl)amino)-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and7-cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.85 (s, 1H), 8.78 (s, 1H), 7.83 (d, J=8.5,1H), 6.75 (d, J=8.5 Hz, 1H), 5.97 (s, 1H), 3.31 (m, 2H), 1.68 (m, 1H),1.08 (m, 1H), 0.82 (d, J=8.5 Hz, 3H), 0.48 (m, 2H), 0.38 (d, J=7.7 Hz,2H), 0.18 (d, J=5.0 Hz, 2H). m/z [M+H]⁺ 402.1.

7-cyclopropyl-4-(methylamino)-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(3-(trifluoromethyl)pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.87 (s, 1H), 8.81 (s, 1H), 7.73 (d, J=8.2 Hz,1H), 6.75 (d, J=8.6 Hz, 1H), 5.98 (s, 1H), 2.95 (s, 3H), 1.69 (br s,1H), 0.83 (d, J=8.5 Hz, 3H), 0.49 (br s, 2H). m/z [M+H]⁺ 362.1.

6-Bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and6-bromo-1-phenyl-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.62 (s, 1H), 7.62 (m, 3H), 7.35 (d, J=7.6 Hz,2H), 6.49 (s, 1H), 3.51 (d, J=6.9, 2H), 1.30 (m, 1H), 0.60 (d, J=7.7 Hz,2H), 0.38 (m, 2H). m/z [M+H]⁺ 456.1, 454.1.

6-Bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and6-bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.65 (s, 1H), 7.56-7.35 (m, 3H), 7.24 (d, J=7.6Hz, 1H), 6.38 (s, 1H), 3.60-3.46 (m, 2H), 2.06 (d, J=2.1 Hz, 3H), 1.30(d, J=6.7 Hz, 1H), 0.61 (d, J=7.7 Hz, 2H), 0.38 (d, J=5.0 Hz, 2H). m/z[M+H]⁺ 468.0, 470.0.

6-Bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using6-bromo-1-(o-tolyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.51 (s, 1H), 7.54-7.44 (m, 3H), 7.33 (d, J=7.6Hz, 1H), 6.39 (s, 1H), 6.24 (s, 1H), 3.16 (s, 3H), 2.07 (s 3H). m/z[M+H]⁺ 430.0, 428.0.

4-(((3-Methoxyisoxazol-5-yl)methyl)amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (3-methoxyisoxazol-5-yl)methanamine and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.30 (d, J=8.2 Hz, 1H), 7.58 (d, J=8.6 Hz, 1H),7.54-7.43 (m, 2H), 7.26 (d, J=7.6 Hz, 1H), 6.69 (s, 1H), 6.18 (s, 1H),3.94 (d, J=2.6 Hz, 3H), 2.05 (d, J=2.6 Hz, 3H). m/z [M+H]⁺ 431.1.

(R)-4-(2-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (R)-pyrrolidin-2-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.43 (t, J=10.3 Hz, 1H), 7.62-7.40 (m, 5H),7.23 (dd, J=19.6, 7.7 Hz, 1H), 6.69 (d, J=14.6 Hz, 1H), 4.15 (s, 2H),4.04 (s, 1H), 3.85 (s, 1H), 2.27-1.97 (m, 6H). m/z [M+H]⁺ 404.1.

(S)-4-(3-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (S)-pyrrolidin-3-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.48 (d, J=8.7 Hz, 1H), 7.51 (q, J=8.9, 7.9 Hz,4H), 7.23 (s, 1H), 6.69 (d, J=5.8 Hz, 1H), 4.15 (s, 2H), 3.77-3.58 (m,2H), 2.61 (s, 1H), 2.22 (s, 1H), 2.05 (dd, J=12.3, 2.5 Hz, 3H). m/z[M+H]⁺ 404.1.

(R)-4-(3-(Hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (R)-pyrrolidin-3-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.48 (d, J=8.5 Hz, 1H), 7.66-7.38 (m, 4H), 7.23(s, 1H), 6.68 (d, J=5.8 Hz, 1H), 4.15 (s, 2H), 3.69 (d, J=12.9 Hz, 2H),2.60 (s, 1H), 2.22 (s, 1H), 2.15-1.99 (m, 3H), 1.93 (s, 1H). m/z [M+H]⁺404.1.

(R)-4-(2-(methoxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using (R)-2-(methoxymethyl)pyrrolidine and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.49-8.22 (m, 1H), 7.50 (dt, J=23.2, 7.9 Hz,4H), 7.31-7.10 (m, 1H), 6.69 (d, J=14.9 Hz, 1H), 4.93 (s, 1H), 4.20-4.03(m, 2H), 3.88 (d, J=8.8 Hz, 1H), 3.74 (d, J=10.1 Hz, 1H), 3.40 (s, 3H),2.18 (d, J=7.1 Hz, 3H), 2.06 (dd, J=30.0, 2.3 Hz, 4H). m/z [M+H]⁺ 418.1.

4-(3-(2-Hydroxyethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using 2-(pyrrolidin-3-yl)ethan-1-ol and1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.48 (s, 1H), 7.61-7.37 (m, 4H), 7.23 (t, J=8.2Hz, 1H), 6.68 (d, J=11.2 Hz, 1H), 3.71 (m, 2H), 2.49 (m, 1H), 2.30 (m,1H), 2.05 (appar d, J=23.1 Hz, 3H), 1.79 (m, 3H). m/z [M+H]⁺ 418.1.

4-(Pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using pyrrolidine and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.96-8.75 (m, 1H), 7.63 (dd, J=8.2, 2.5 Hz,1H), 7.48-7.26 (m, 3H), 7.14 (d, J=7.5 Hz, 1H), 4.04 (m, J=61.3 Hz, 4H),2.13 (m, 4H), 2.02 (d, J=2.5 Hz, 3H). m/z [M+H]⁺ 375.2.

(R)-4-(2-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using (R)-pyrrolidin-2-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.83 (t, J=10.0 Hz, 1H), 8.18 (s, 1H), 7.63(dd, J=8.4, 2.4 Hz, 1H), 7.47-7.28 (m, 3H), 7.14 (dd, J=23.5, 7.7 Hz,1H), 4.78 (s, 1H), 4.21-3.99 (m, 3H), 3.83 (ddt, J=11.4, 5.9, 2.8 Hz,1H), 2.19 (dd, J=19.4, 10.9 Hz, 3H), 2.13-2.04 (m, 2H), 1.97 (d, J=2.5Hz, 2H). m/z [M+H]⁺ 405.00.

(R)-4-(3-(hydroxymethyl)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using (R)-pyrrolidin-3-ylmethanol and1-(o-tolyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, MeOD) δ 8.86 (d, J=8.3 Hz, 1H), 8.40 (s, 1H), 7.63 (d,J=8.6 Hz, 1H), 7.46-7.25 (m, 3H), 7.14 (t, J=7.1 Hz, 1H), 4.07 (m, 4H),3.70 (m, 2H), 2.62 (m, 1H), 2.21 (m, 1H), 2.08-1.86 (m, 4H). m/z [M+H]⁺405.00.

4-Amino-1-(2-chlorophenyl)-7-cyclopropylquinazolin-2(1H)-one wasprepared by substituting was prepared by using ammonia (7 M solution inMeOH) and 1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.15-7.84 (m, 3H), 7.73 (dt, J=6.1, 2.8 Hz,1H), 7.62-7.39 (m, 3H), 6.80 (d, J=8.4 Hz, 1H), 6.02 (s, 1H), 1.91-1.73(m, 1H), 0.94 (d, J=8.4 Hz, 2H), 0.61 (d, J=6.5 Hz, 2H). m/z [M+H]⁺312.00.

1-(2-chlorophenyl)-7-cyclopropyl-4-(isopropylamino)quinazolin-2(1H)-onewas prepared by using isopropylamine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.12 (t, J=9.1 Hz, 2H), 7.72 (q, J=3.6, 2.2Hz, 1H), 7.63-7.39 (m, 3H), 6.82 (d, J=8.4 Hz, 1H), 6.00 (s, 1H), 4.49(q, J=6.8 Hz, 1H), 1.81 (s, 1H), 1.34-1.17 (m, 5H), 0.94 (d, J=8.3 Hz,2H), 0.59 (s, 2H). m/z [M+H]⁺ 354.20.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-onewas prepared by using (1S,2R)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.74(h, J=4.0, 3.2 Hz, 1H), 7.63-7.40 (m, 3H), 6.84 (d, J=8.4 Hz, 1H), 6.04(s, 1H), 4.85 (d, J=65.2 Hz, 1H), 3.63 (dt, J=20.5, 6.8 Hz, 1H), 3.05(d, J=6.8 Hz, 1H), 1.90-1.73 (m, 1H), 1.45-1.14 (m, 3H), 0.95 (d, J=8.3Hz, 2H), 0.60 (d, J=6.5 Hz, 2H). m/z [M+H]⁺ 370.00.

1-(2-chlorophenyl)-7-cyclopropyl-4-(isoxazol-4-ylamino)quinazolin-2(1H)-onewas prepared by using isoxazol-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.48 (s, 1H), 9.43 (s, 1H), 8.89 (d, J=1.9Hz, 1H), 8.22 (d, J=8.4 Hz, 1H), 7.85-7.42 (m, 4H), 6.95 (d, J=8.4 Hz,1H), 6.68 (s, 1H), 6.12 (s, 1H), 1.86 (q, J=7.6, 7.1 Hz, 1H), 0.98 (d,J=8.3 Hz, 2H), 0.66 (q, J=8.0, 6.6 Hz, 2H). m/z [M+H]⁺ 379.00.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(isothiazol-4-ylamino)quinazolin-2(1H)-onewas prepared by using thioisoxazol-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.65 (s, 1H), 9.36 (s, 1H), 8.96 (s, 1H),8.34 (d, J=8.5 Hz, 1H), 7.87-7.69 (m, 1H), 7.57 (ddt, J=23.9, 5.8, 2.4Hz, 3H), 6.96 (d, J=8.3 Hz, 1H), 6.12 (s, 1H), 1.99-1.77 (m, 1H), 0.99(d, J=8.3 Hz, 2H), 0.66 (d, J=6.8 Hz, 2H). m/z [M+H]⁺ 395.00.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((2-(trifluoromethyl)pyridin-4-yl)amino)quinazolin-2(1H)-onewas prepared by using 2-(trifluoromethyl)pyridin-4-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 10.33 (s, 1H), 8.73 (d, J=5.3 Hz, 1H), 8.56(s, 1H), 8.41 (d, J=13.3 Hz, 2H), 7.79 (s, 1H), 7.59 (d, J=17.1 Hz, 3H),7.00 (d, J=8.5 Hz, 1H), 6.17 (s, 1H), 1.91 (s, 1H), 1.01 (d, J=8.4 Hz,2H), 0.68 (s, 2H). m/z [M+H]⁺ 457.00.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(imidazo[1,2-a]pyridin-5-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, Methanol-d₄) δ 8.42 (d, J=2.0 Hz, 1H), 7.85 (dd, J=8.5,2.1 Hz, 1H), 7.70 (d, J=9.2 Hz, 1H), 7.57-7.29 (m, 3H), 7.11-6.99 (m,1H), 6.85 (d, J=8.5 Hz, 1H), 6.10 (s, 1H), 3.05 (d, J=2.1 Hz, 3H), 1.69(t, J=6.8 Hz, 1H), 0.86 (d, J=8.7 Hz, 2H), 0.47 (d, J=15.0 Hz, 2H). m/z[M+H]⁺ 332.00.

7-Cyclopropyl-4-((cyclopropylmethyl)amino)-1-(pyrazin-2-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and7-cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79 (d, J=2.8 Hz, 2H), 8.69 (d, J=6.7 Hz,1H), 8.09 (d, J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz, 1H), 6.21 (s, 1H), 3.39(d, J=6.4 Hz, 3H), 1.87 (s, 1H), 1.20 (s, 2H), 0.95 (d, J=7.9 Hz, 2H),0.65 (d, J=5.1 Hz, 2H), 0.49 (d, J=7.9 Hz, 2H), 0.31 (d, J=4.9 Hz, 2H).m/z [M+H]⁺ 334.20.

7-Cyclopropyl-4-(methylamino)-1-(3-methylpyrazin-2-yl)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d6) δ 8.78-8.53 (m, 3H), 8.02 (dd, J=8.4, 2.1 Hz,1H), 6.84 (d, J=8.5 Hz, 1H), 6.09 (s, 1H), 3.06-2.92 (m, 3H), 2.29 (d,J=2.1 Hz, 3H), 1.87 (q, J=7.4 Hz, 1H), 0.94 (d, J=6.8 Hz, 2H), 0.65 (s,2H). m/z [M+H]⁺ 308.20.

7-cyclopropyl-4-((cyclopropylmethyl)amino)-1-(3-methylpyrazin-2-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and7-cyclopropyl-1-(3-methylpyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.79-8.53 (m, 3H), 8.20-8.04 (m, 1H), 6.85(d, J=8.4 Hz, 1H), 6.09 (s, 1H), 3.61 (dt, J=38.2, 6.6 Hz, 2H), 3.44 (d,J=7.8 Hz, 2H), 2.29 (d, J=2.2 Hz, 3H), 1.86 (d, J=7.3 Hz, 1H), 1.82-1.68(m, 1H), 1.64-1.51 (m, 1H), 1.22 (d, J=8.0 Hz, 2H), 0.95 (t, J=6.1 Hz,2H), 0.66 (s, 2H), 0.50 (d, J=7.9 Hz, 2H), 0.31 (d, J=4.8 Hz, 2H). m/z[M+H]⁺ 348.20.

7-Cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.00 (d, J=7.1 Hz, 1H), 8.76 (s, 1H), 8.40(s, 1H), 8.17 (s, 1H), 8.13-7.95 (m, 1H), 7.96-7.81 (m, 1H), 7.36 (d,J=6.9 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.56 (s, 1H), 5.72 (q, J=12.2,11.5 Hz, 1H), 4.44-4.22 (m, 1H), 3.92 (t, J=6.8 Hz, 2H), 3.13-3.05 (m,2H), 3.04-2.96 (m, 2H), 2.55 (d, J=2.0 Hz, 1H), 2.36 (d, J=12.5 Hz, 1H),1.87 (s, 1H), 1.24 (t, J=7.0 Hz, 5H), 0.94 (d, J=8.0 Hz, 2H), 0.70 (d,J=5.1 Hz, 2H). m/z [M+H]⁺ 332.00.

4-((Cyclopropylmethyl)amino)-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using cyclopropylmethylamine and5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J=4.7 Hz, 1H), 8.45-8.28 (m, 1H),8.20 (d, J=8.4 Hz, 1H), 8.02 (t, J=6.2 Hz, 1H), 7.66 (d, J=11.8 Hz, 1H),6.41 (s, 1H), 3.59-3.37 (m, 2H), 1.27 (s, 1H), 0.59-0.25 (m, 4H). m/z[M+H]⁺ 447.00.

5-fluoro-4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine formethyl amine and using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 7.53 (d, J=5.7 Hz, 1H),7.46-7.35 (m, 2H), 7.29 (d, J=6.2 Hz, 1H), 4.77 (d, J=63.1 Hz, 1H), 2.37(d, J=4.4 Hz, 2H), 1.41-1.22 (m, 2H), 1.12-0.96 (m, 3H), 0.75 (d, J=23.4Hz, 2H). m/z [M+H]⁺ 396.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidine-6-carbonitrilewas prepared by substituting cyclopropylmethanamine for methyl amine andusing1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 8.35 (s, 1H), 7.50 (dd, J=5.1, 1.8 Hz,1H), 7.41-7.33 (m, 2H), 6.89 (s, 1H), 3.56-3.39 (m, 2H), 2.42-2.32 (m,1H), 1.18-1.09 (m, 1H), 1.09-0.95 (m, 2H), 0.75 (d, J=23.2 Hz, 2H), 0.56(d, J=7.0 Hz, 2H), 0.32-0.23 (m, 2H). m/z [M+H]⁺ 392.1.

6-bromo-4-((cyclopropylmethyl)(methyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting 1-cyclopropyl-N-methylmethanamine formethyl amine and using6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, Chloroform-d) δ 8.16 (s, 1H), 7.56 (t, J=7.3 Hz, 2H),7.53-7.46 (m, 1H), 7.24 (s, 2H), 6.87 (s, 1H), 3.65 (d, J=6.4 Hz, 2H),3.45 (s, 3H), 1.26-1.14 (m, 1H), 0.68 (d, J=7.4 Hz, 2H), 0.35 (d, J=4.3Hz, 2H). m/z [M+H]⁺ 452.0, 454.0.

6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared substituting cyclopropylmethanamine for methyl amine andusing 6-bromo-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, Chloroform-d) δ 8.22 (s, 1H), 7.55 (t, J=7.3 Hz, 2H),7.51-7.45 (m, 1H), 7.25-7.22 (m, 3H), 6.85 (s, 1H), 3.51 (d, J=7.0 Hz,2H), 1.22-1.11 (m, 1H), 0.57 (d, J=7.1 Hz, 2H), 0.31 (d, J=4.0 Hz, 2H).m/z [M+H]⁺ 438.0, 440.0.

7-cyclopropyl-4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting cyclopropylmethanamine for methyl amine andusing7-cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 7.95 (s, 1H), 7.43-7.34 (m, 3H), 7.10(d, J=7.3 Hz, 1H), 5.90 (s, 1H), 3.56 (t, J=7.9 Hz, 2H), 2.24-2.16 (m,1H), 2.04 (s, 3H), 1.24-1.15 (m, 1H), 1.09 (d, J=8.2 Hz, 2H), 0.65 (d,J=7.5 Hz, 2H), 0.49 (d, J=4.5 Hz, 2H), 0.35 (d, J=4.5 Hz, 2H). m/z[M+H]⁺ 371.2.

7-cyclopropyl-4-(methylamino)-2-oxo-1-(o-tolyl)-1,2-dihydroquinazoline-6-carbonitrilewas prepared using7-cyclopropyl-2,4-dioxo-1-(o-tolyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 8.12 (s, 1H), 7.43-7.31 (m, 3H), 7.12(d, J=6.9 Hz, 1H), 5.90 (s, 1H), 3.19 (s, 3H), 2.23-2.14 (m, 1H), 2.05(s, 3H), 1.09 (d, J=7.8 Hz, 2H), 0.52-0.45 (m, 2H). m/z [M+H]⁺ 331.2.

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(1,1-difluoroethyl)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting cyclopropylmethanamine for methyl amine andusing using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 9.01 (s, 1H), 7.76 (d, J=3.3Hz, 1H), 7.59 (dd, J=8.6, 4.9 Hz, 3H), 6.45 (s, 1H), 3.49-3.40 (m, 2H),1.96 (t, J=19.1 Hz, 3H), 1.24-1.16 (m, 1H), 0.53 (d, J=7.1 Hz, 2H),0.36-0.30 (m, 2H). m/z [M+H]⁺ 415.0.

1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 9.08 (s, 1H), 8.86 (s, 1H), 7.76 (d, J=3.1Hz, 1H), 7.63-7.57 (m, 2H), 7.57-7.50 (m, 1H), 6.45 (s, 1H), 3.01 (s,3H), 1.95 (t, J=19.4 Hz, 3H). m/z [M+H]⁺ 375.0.

6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((1S,2R)-2-fluorocyclopropyl)-amino)quinazolin-2(1H)-onewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine formethylamine and using6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (s, 1H), 8.76 (s, 1H), 7.76 (d, J=4.0Hz, 1H), 7.58 (s, 2H), 7.08 (s, 1H), 6.47 (s, 1H), 4.89 (d, J=62.4 Hz,1H), 3.10 (s, 1H), 1.96 (t, J=19.2 Hz, 3H), 1.42-1.21 (m, 2H). m/z[M+H]⁺ 472.0, 474.0.

6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared using6-bromo-1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (s, 1H), 8.61 (s, 1H), 7.75 (dd, J=5.4,2.3 Hz, 1H), 7.60-7.54 (m, 2H), 7.54-7.49 (m, 1H), 6.96 (s, 1H), 6.45(s, 1H), 2.99 (s, 3H), 1.96 (t, J=19.0 Hz, 3H). m/z [M+H]⁺ 428.0, 430.0.

1-(2-chlorophenyl)-7-cyclopropyl-4-((2,2-difluoroethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting 2,2-difluoroethan-1-amine for methylamineand using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 9.10 (s, 1H), 8.75 (s, 1H), 7.75 (d, J=6.5Hz, 1H), 7.65-7.54 (m, 2H), 7.50 (d, J=6.6 Hz, 1H), 6.27 (t, J=56.7 Hz,1H), 5.76 (s, 1H), 3.95 (dq, J=31.0, 15.5, 14.6 Hz, 2H), 2.16 (p, J=7.0,6.5 Hz, 1H), 1.09 (d, J=7.3 Hz, 2H), 0.41 (s, 2H). m/z [M+H]⁺ 401.1.

1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting cyclopropylmethanamine for methylamine andusing1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 9.18 (s, 1H), 9.12 (s, 1H), 7.78 (d, J=4.2Hz, 1H), 7.61 (d, J=8.6 Hz, 3H), 6.57 (s, 1H), 3.44 (d, J=14.3 Hz, 2H),1.26-1.14 (m, 1H), 0.54 (d, J=7.3 Hz, 2H), 0.40-0.29 (m, 2H). m/z [M+H]⁺419.0.

1-(2-chlorophenyl)-4-(methylamino)-2-oxo-7-(trifluoromethyl)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using1-(2-chlorophenyl)-2,4-dioxo-7-(trifluoromethyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (s, 1H), 8.97 (s, 1H), 7.78 (d, J=4.7Hz, 1H), 7.65-7.54 (m, 3H), 6.57 (s, 1H), 3.03 (s, 3H). m/z [M+H]⁺379.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-(hydroxymethyl)cyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting (1-aminocyclopropyl)methanol formethylamine and using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.49 (s, 1H), 7.74 (d, J=6.4Hz, 1H), 7.57 (dd, J=6.3, 2.4 Hz, 2H), 7.46 (d, J=6.7 Hz, 1H), 5.71 (s,1H), 4.98 (t, J=4.5 Hz, 1H), 3.90-3.76 (m, 2H), 2.31 (dd, J=20.7, 10.0Hz, 4H), 2.19-2.09 (m, 1H), 1.90-1.74 (m, 2H), 1.08 (d, J=7.0 Hz, 2H),0.39 (s, 2H).

4-Amino-1-(2-chlorophenyl)-7-cyclopropyl-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting ammonia for methylamine and using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 8.46 (s, 1H), 7.68 (d, J=7.5 Hz, 1H),7.55 (dt, J=15.5, 7.4 Hz, 2H), 7.37 (d, J=7.3 Hz, 1H), 5.88 (s, 1H),2.32-2.23 (m, 1H), 1.15 (d, J=8.3 Hz, 2H), 0.59-0.49 (m, 2H). m/z [M+H]⁺337.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((trans)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting (trans)-2-fluorocyclopropan-1-amine formethylamine and using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, Chloroform-d) δ 8.59 (d, J=12.0 Hz, 1H), 7.63 (d, J=3.9Hz, 1H), 7.50 (s, 2H), 7.43-7.31 (m, 1H), 5.85 (s, 1H), 5.01-4.75 (m,1H), 3.45 (d, J=16.0 Hz, 1H), 2.20 (s, 1H), 1.52 (d, J=25.1 Hz, 2H),1.27 (s, 1H), 1.11 (d, J=7.2 Hz, 2H), 0.52 (s, 2H). m/z [M+H]⁺ 395.0.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine formethyl amine and using1-(2-chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ 8.75 (d, J=11.5 Hz, 2H), 7.75 (d, J=6.5 Hz,1H), 7.58 (d, J=8.3 Hz, 2H), 7.56-7.45 (m, 1H), 5.76 (s, 1H), 4.88 (d,J=66.7 Hz, 1H), 3.09 (d, J=7.3 Hz, 1H), 2.20-2.09 (m, 1H), 1.40-1.20 (m,2H), 1.09 (d, J=8.0 Hz, 2H), 0.41 (s, 2H). m/z [M+H]⁺ 395.0.

6-Bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-quinazolin-2(1H)-onewas prepared by substituting (1S,2R)-2-fluorocyclopropan-1-amine formethylamine and using6-bromo-1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, Chloroform-d) δ 7.77 (s, 1H), 7.64-7.58 (m, 1H),7.50-7.42 (m, 2H), 7.34 (d, J=3.3 Hz, 1H), 6.16 (s, 1H), 5.93 (s, 1H),4.85 (d, J=63.8 Hz, 1H), 3.35 (s, 1H), 2.11 (p, J=7.0 Hz, 1H), 1.33 (dd,J=16.0, 7.5 Hz, 1H), 1.20-1.04 (m, 1H), 0.98 (d, J=8.0 Hz, 2H),0.46-0.36 (m, 2H). m/z [M+H]⁺ 448.0/450.0.

7-(1,1-Difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.73 (d, J=7. ∝Hz, 2H), 8.23 (d, J=8.6 Hz,1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.41 (d, J=7.9 Hz, 1H),6.85 (d, J=7.1 Hz, 1H), 6.73 (s, 1H), 3.03-2.95 (m, 3H), 1.87 (t, J=19.0Hz, 3H). m/z [M+H]⁺ 356.0.

4-Amino-7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-onewas prepared by substituting ammonia for methylamine and using7-(1,1-difluoroethyl)-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (d, J=7.4 Hz, 1H), 8.26 (d, J=8.6 Hz,2H), 8.15 (s, 1H), 8.08 (s, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.39 (d,J=7.9 Hz, 1H), 6.85 (d, J=7.4 Hz, 1H), 6.72 (s, 1H), 1.87 (t, J=19.1 Hz,3H). m/z [M+H]⁺ 342.1.

1-(3-Chloropyridin-2-yl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.93-8.84 (m, 1H), 8.67 (d, J=4.4 Hz, 1H),8.28 (d, J=8.6 Hz, 2H), 7.70-7.63 (m, 1H), 7.46 (d, J=8.3 Hz, 1H), 6.32(s, 1H), 3.02 (d, J=3.3 Hz, 3H), 1.88 (t, J=19.0 Hz, 3H). m/z [M+H]⁺351.0.

4-Amino-1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazolin-2(1H)-onewas prepared by substituting ammonia for methylamine and using1-(3-chloropyridin-2-yl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=4.4 Hz, 1H), 8.41 (s, 1H), 8.30(t, J=8.9 Hz, 3H), 7.70-7.64 (m, 1H), 7.44 (d, J=8.4 Hz, 1H), 6.32 (s,1H), 1.88 (t, J=19.0 Hz, 3H). m/z [M+H]⁺ 337.0.

1-(3-Chloropyridin-2-yl)-7-ethyl-4-(methylamino)quinazolin-2(1H)-one wasprepared by using1-(3-chloropyridin-2-yl)-7-ethylquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (t, J=5.8 Hz, 2H), 8.22 (d, J=8.1 Hz,1H), 8.02 (d, J=8.6 Hz, 1H), 7.65-7.57 (m, 1H), 7.09 (d, J=7.8 Hz, 1H),6.02 (s, 1H), 2.96 (d, J=3.9 Hz, 3H), 2.51 (s, 2H), 1.01 (t, J=7.4 Hz,3H). m/z [M+H]⁺ 315.0.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80-8.74 (m, 1H), 8.23 (d, J=8.5 Hz, 1H),7.76-7.70 (m, 1H), 7.59-7.53 (m, 2H), 7.49 (d, J=3.1 Hz, 1H), 7.41 (d,J=9.2 Hz, 1H), 6.35 (s, 1H), 2.99 (d, J=3.5 Hz, 3H), 1.85 (t, J=18.9 Hz,3H). m/z [M+H]⁺ 350.1.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(isoxazol-4-ylamino)quinazolin-2(1H)-onewas prepared by substituting isoxazol-4-amine for methylamine and using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.88 (s, 1H), 8.44 (d, J=8.0Hz, 1H), 7.79-7.74 (m, 1H), 7.62-7.50 (m, 4H), 6.41 (s, 1H), 1.87 (t,J=18.8 Hz, 3H). m/z [M+H]⁺ 403.0.

1-(2-Chlorophenyl)-7-(1,1-difluoroethyl)-4-(amino)quinazolin-2(1H)-onewas prepared by substituting ammonia for methylamine and using1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.34-8.24 (m, 2H), 8.18 (s, 1H), 7.76-7.70(m, 1H), 7.59-7.53 (m, 2H), 7.53-7.47 (m, 1H), 7.39 (d, J=8.4 Hz, 1H),6.34 (s, 1H), 1.85 (t, J=18.9 Hz, 3H). m/z [M+H]⁺ 336.1.

1-(2-Chlorophenyl)-4-(methylamino)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared using1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.78 (d, J=3.5 Hz, 1H), 8.25 (d, J=8.5 Hz,1H), 7.76-7.70 (m, 1H), 7.60-7.52 (m, 2H), 7.52-7.46 (m, 1H), 7.24 (d,J=8.4 Hz, 1H), 6.07 (s, 1H), 2.98 (d, J=3.3 Hz, 3H). m/z [M+H]⁺ 370.1.

7-Chloro-1-(imidazo[1,2-a]pyridin-5-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared using7-chloro-1-(imidazo[1,2-a]pyridin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.90 (s, 1H), 8.17 (d, J=8.3 Hz, 1H), 7.76(d, J=8.3 Hz, 1H), 7.63 (s, 1H), 7.57 (s, 1H), 7.45-7.39 (m, 1H), 7.36(d, J=8.5 Hz, 1H), 7.11 (d, J=6.9 Hz, 1H), 6.33 (s, 1H), 3.01 (d, J=3.5Hz, 3H). m/z [M+H]⁺ 326.0.

7-chloro-4-((2,2-difluoroethyl)amino)-1-(imidazo[1,2-a]pyridin-7-yl)quinazolin-2(1H)-onewas prepared by substituting 2,2-difluoroethan-1-amine for methylamineand using7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.97 (t, J=6.2 Hz, 1H), 8.71 (d, J=7.6 Hz,1H), 8.21 (d, J=8.9 Hz, 1H), 8.07 (s, 1H), 7.68 (s, 1H), 7.64 (s, 1H),7.34 (d, J=8.8 Hz, 1H), 6.84 (d, J=7.0 Hz, 1H), 6.70 (s, 1H), 6.43-6.09(m, 1H), 3.92 (t, J=14.6 Hz, 2H). m/z [M+H]⁺ 376.0.

7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-chloro-1-(imidazo[1,2-a]pyridin-7-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.70 (dd, J=11.0, 5.5 Hz, 2H), 8.13 (s, 1H),8.07 (s, 1H), 7.68 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=8.7 Hz, 1H), 6.83(d, J=7.0 Hz, 1H), 6.66 (s, 1H), 2.98 (d, J=3.7 Hz, 3H). m/z [M+H]⁺326.0.

7-bromo-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)quinazolin-2(1H)-onewas prepared using7-bromo-1-(2-chlorophenyl)-6-fluoroquinazoline-2,4(1H,3H)-dione.

(R)-1-(2-Bromophenyl)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)quinazolin-2(1H)-onewas prepared by using (R)-pyrrolidin-3-ol and1-(2-bromophenyl)-7-chloroquinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.22 (br s, 1H), 7.90-7.88 (m, 1H),7.63-7.59 (m, 1H), 7.51-7.46 (m, 2H), 7.26-7.23 (m, 1H), 6.21 (dd,J=4.4, 2.0 Hz, 1H), 5.13 (dd, J=11.6, 3.2 Hz, 1H), 4.42 (s, 1H),4.02-3.90 (m, 3H), 3.71-3.68 (m, 1H), 3.05-2.98 (m, 2H). m/z [M+H]⁺420.0.

1-(2-Chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one—singleenantiomer with unknown stereochemistry was prepared by usingtrans-2-fluorocyclopropan-1-amine and using1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.SFC purification (20% MeOH, R,R WHELK-01, peak 1)

¹H NMR (400 MHz, DMSO-d₆) (8.93 (d, J=10.8 Hz, 1H), 8.77 (d, J=8.0 Hz,1H), 7.79 (d, J=8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.44 (m, 3H),4.96-4.79 (m, 1H), 3.50-3.47 (m, 1H), 1.61-1.51 (m, 1H), 1.27-1.24 (m,1H). m/z [M+H]⁺ 399.4.

1-(2-Chlorophenyl)-4-(((trans)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one—singleenantiomer with unknown stereochemistry was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.SFC purification (20% MeOH, R,R WHELK-01, peak 2)

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (d, J=10.8 Hz, 1H), 8.77 (d, J=8.0 Hz,1H), 7.79 (d, J=8.0 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.44 (m, 3H),4.96-4.79 (m, 1H), 3.50-3.47 (m, 1H), 1.61-1.51 (m, 1H), 1.27-1.24 (m,1H). m/z [M+H]⁺ 399.4.

1-(2-Chloropyridin-3-yl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-(2-chloropyridin-3-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.19 (s, 1H), 8.81 (s, J=8.0 Hz, 1H), 8.50(dd, J=4.5 Hz, J=1.5 Hz, 1H), 7.99 (dd, J=8.0 Hz, 2.0 Hz, 1H), 7.84 (d,J=8.5 Hz, 1H), 7.62 (m, 1H), 3.04 (s, 3H). m/z [M+H]⁺ 356.3

4-(Methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.20 (d, J=4.5 Hz, 1H), 8.85-8.81 (m, 2H),8.08 (d, J=8.0 Hz, 1H), 7.93 (dd, J=8.0, 4.5 Hz, 1H), 7.83 (d, J=8.0 Hz,1H), 3.04 (d, J=4.5 Hz, 3H). m/z [M+H]⁺ 390.4.

7-Cyclopropyl-1-(2-methylpyridin-3-yl)-4-((3-morpholinopropyl)amino)quinazolin-2(1H)-onewas prepared by using 3-morpholinopropan-1-amine and7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (dd, J=5.0, 1.5 Hz, 1H), 8.46 (t, J=5.5Hz, 1H), 8.03 (d, J=8.5 Hz 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.45-7.42(m, 1H), 6.82 (dd, J=8.5, 1.5 Hz, 1H), 6.03 (s, 1H), 3.58-3.49 (m, 6H),2.39-2.36 (m, 6H), 2.13 (s, 3H), 1.84-1.80 (m, 3H), 0.94-0.92 (m, 2H),0.62-0.57 (m, 2H). m/z [M+H]⁺ 420.31.

3-((7-Cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N-methylpropanamidewas prepared by using 3-amino-N-methylpropanamide and7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 9.74 (br s, 1H), 8.75 (dd, 4.8, 1.2 Hz 1H),8.00 (d, J=8.8 Hz, 1H), 7.66 (dd, J=8, 1.6 Hz, 1H), 7.47 (dd, 8.0, 5.2Hz, 1H), 6.83 (dd, J=8.4, 1.2 Hz, 1H), 6.76 (br s, 1H), 6.13 (s, 1H),4.01 (t, J=5.6 Hz, 2H), 2.83 (d, J=4.8 Hz, 3H), 2.79 (t, J=5.6 Hz, 2H),2.40 (s, 3H), 1.79-1.75 (m, 1H), 1.07-1.02 (m, 2H), 0.69-0.65 (m, 2H).m/z [M+H]⁺ 378.47.

2-((7-Cyclopropyl-1-(2-methylpyridin-3-yl)-2-oxo-1,2-dihydroquinazolin-4-yl)amino)-N,N-dimethylethane-1-sulfonamidewas prepared by using 2-amino-N,N-dimethylethane-1-sulfonamide and7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.67 (t, J=5.5 Hz, 1H), 8.60-8.58 (dd, J=5,1.5 Hz, 1H), 7.97 (d, J=8.58.5 Hz, 1H), 7.69-7.67 (dd, J=8, 1.5 Hz, 1H),7.49-7.47 (m, 1H), 6.87-6.85 (dd, J=8.5, 1.5 Hz, 1H), 3.90-3.84 (m, 2H),3.46-3.42 (m, 2H), 2.81 (s, 6H), 2.15 (s, 3H), 1.85-1.82 (m, 1H),0.98-0.95 (m, 2H), 0.63-0.58 (m, 2H). m/z [M+H]⁺ 428.49.

7-Cyclopropyl-4-((2-(dimethylamino)ethyl)amino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-onewas prepared by using N1,N1-dimethylethane-1,2-diamine and7-cyclopropyl-1-(2-methylpyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (8.57 (dd, J=4.5, 1.5 Hz, 1H), 8.38 (t, J=5Hz, 1H), 8.03 (d, J=8.5 Hz 1H), 7.66 (dd, J=8.0, 1.5 Hz, 1H), 7.44 (dd,J=8.0, 5 Hz, 1H), 6.83 (dd, J=8.5, 1.5 Hz, 1H), 6.03 (s, 1H), 3.66-3.53(m, 2H), 2.54-2.50 (m, 2H), 2.23 (s, 6H), 2.10 (s, 3H), 1.85-1.81 (m,1H), 0.94-0.92 (m, 2H), 0.62-0.58 (m, 2H). m/z [M−H]⁺ 362.52.

3-((1-(2-Chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)-N-methylpropanamidewas prepared by using 3-amino-N-methylpropanamide and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (9.13 (s, 1H), 8.85 (d, J=8.0 Hz, 1H), 7.91(d, J=4.0 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.65-7.63 (m, 1H), 7.49-7.43(m, 3H), 3.72-3.72 (m, 2H), 2.60 (d, J=4.5 Hz, 3H), 2.54-2.52 (m, 2H).m/z [M+H]⁺ 426.4.

2-((1-(2-chlorophenyl)-2-oxo-7-(trifluoromethyl)-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)amino)-N,N-dimethylethanesulfonamidewas prepared by using 2-amino-N,N-dimethylethane-1-sulfonamide and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆): δ 8.98 (br s, 1H), 8.85 (d, J=10 Hz, 1H),7.80 (d, J=10 Hz, 1H), 7.64-7.61 (m, 1H), 7.49-7.43 (m, 3H), 3.69-3.65(m, 2H), 3.58 (t, J=5.5 Hz, 4H), 2.62 (d, J=8.5 Hz, 2H), 2.5 (m, 4H).

4-(((trans)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one,single unknown enantiomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. SFCpurification (40% MeOH, Chiralpak IC, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.62-7.59 (m, 2H), 7.55-7.51(m, 1H), 7.33-7.31 (m, 2H), 7.07 (d, J=1.0 Hz, 1H), 6.14 (d, J=1.0 Hz,1H), 5.01-4.86 (m, 1H), 4.08 (s, 3H), 3.43-3.41 (m, 1H), 1.54-1.47 (m,1H), 1.30-1.23 (m, 1H). m/z [M+H]⁺ 394.4.

4-(((trans)-2-fluorocyclopropyl)amino)-5-methoxy-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one,single unknown enantiomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and5-methoxy-1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione. SFCpurification (40% MeOH, Chiralpak IC, peak 2).

¹H NMR (500 MHz, DMSO-d₆) δ 8.27 (s, 1H), 7.62-7.59 (m, 2H), 7.55-7.51(m, 1H), 7.33-7.31 (m, 2H), 7.07 (d, J=1.0 Hz, 1H), 6.14 (d, J=1.0 Hz,1H), 5.01-4.86 (m, 1H), 4.08 (s, 3H), 3.43-3.41 (m, 1H), 1.54-1.47 (m,1H), 1.30-1.23 (m, 1H). m/z [M+H]⁺ 394.4.

7-Cyclopropyl-4-(methylamino)-2-oxo-1-(2-(trifluoromethyl)phenyl)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using7-cyclopropyl-2,4-dioxo-1-(2-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (d, J=4 Hz, 1H), 8.59 (s, 1H), 7.98 (d,J=7.5 Hz, 1H), 7.91 (t, J=7.5 Hz, 1H), 7.78 (t, J=8 Hz, 1H), 7.52 (d,J=8 Hz, 1H), 5.65 (s, 1H), 2.99 (s, 3H), 2.14-2.11 (m, 1H), 1.08-1.03(m, 2H), 0.40-0.37 (dd, J=10.5, 2 Hz, 2H). m/z [M+H]⁺ 385.44.

7-Cyclopropyl-1-(2-cyclopropylphenyl)-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using7-cyclopropyl-1-(2-cyclopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) δ 8.69 (d, J=4.0 Hz, 1H), 8.58 (s, 1H),7.44-7.41 (m, 1H), 7.36-7.33 (m, 1H), 7.16-7.11 (m, 2H), 5.76 (s, 1H),2.98 (d, J=4.0 Hz, 3H), 2.13-2.11 (in, 1H), 1.40-1.39 (m, 1H), 1.09-1.04(m, 2H), 0.79-0.71 (m, 2H), 0.59-0.57 (m, 1H), 0.36-0.31 (m, 3H). m/z[M+H]⁺ 357.40.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile,single unknown atropisomer was prepared by using1-(2-bromophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.SFC purification (30% MeOH, (R,R) WHELK-01, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.79 (s, 1H), 8.60 (s, 1H), 7.88 (dd, 8.0,1.0 Hz 1H), 7.62-7.59 (m, 1H), 7.51-7.45 (m, 2H), 5.71 (s, 1H), 2.98 (s,3H), 2.16-2.11 (m, 1H), 1.09-1.05 (m, 2H), 0.42-0.39 (m, 2H). m/z [M+H]⁺395.41.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrile,single unknown atropisomer was prepared by using1-(2-bromophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.SFC purification (30% MeOH, (R,R) WHELK-01, peak 2).

¹H NMR (500 MHz, DMSO-d₆) (8.79 (s, 1H), 8.60 (s, 1H), 7.88 (dd, 8.0,1.0 Hz 1H), 7.62-7.59 (m, 1H), 7.51-7.45 (m, 2H), 5.71 (s, 1H), 2.98 (s,3H), 2.16-2.11 (m, 1H), 1.09-1.05 (m, 2H), 0.42-0.39 (m, 2H). m/z [M+H]⁺395.41.

6-Bromo-7-cyclopropyl-4-(methylamino)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using6-bromo-7-cyclopropyl-1-(2-(trifluoromethyl)pyridin-3-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (8.92-8.91 (m, 1H), 8.75 (d, J=4.0 Hz, 1H),8.45 (s, 1H), 8.10-8.08 (m, 1H), 7.98 (dd, J=8.0, 5.0 Hz, 1H), 5.70 (s,1H), 2.97 (d, J=4.5 Hz, 3H), 2.10-2.05 (m, 1H), 0.99-0.95 (m, 2H),0.35-0.28 (m, 2H). m/z [M+H]⁺ 439.4.

6-Bromo-1-(2-chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-onewas prepared by using6-bromo-1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (8.75 (d, J=4.5 Hz, 1H), 8.58 (dd, J=5.0, 2.0Hz, 1H), 8.46 (s, 1H), 8.02 (dd, J=8.0, 2.0 Hz, 1H), 7.67 (dd, J=8.0,5.0 Hz, 1H), 5.78 (s, 1H), 2.97 (d, J=4.5 Hz, 3H), 2.11-2.06 (m, 1H),1.00-0.96 (m, 2H), 0.37-0.34 (m, 2H). m/z [M+H]⁺ 405.2.

1-(2-Chlorophenyl)-6-(difluoromethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-(2-Chlorophenyl)-6-(difluoromethyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.19 (d, J=4.5 Hz, 1H), 8.74 (s, 1H),7.79-7.77 (m, 1H), 7.62-7.56 (m, 3H), 7.27 (t, J=53.5 Hz, 1H), 6.54 (s,1H), 3.02 (d, J=4.4 Hz, 3H). m z [M+H]⁺ 404.4.

1-(2-Chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)-4-(methylamino)quinazolin-2(1H)-onewas prepared by using1-(2-Chlorophenyl)-7-cyclopropyl-6-(difluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=4.4 Hz, 1H), 8.36 (s, 1H),7.75-7.73 (m, 1H), 7.58-7.54 (m, 2H), 7.49-7.21 (m, 2H), 5.82 (s, 1H),2.98 (d, J=4.4 Hz, 3H), 2.09-2.07 (m, 1H), 0.95-0.92 (m, 2H), 0.32-0.31(m, 2H). m/z [M+H]⁺ 376.4.

1-(2-Chlorophenyl)-6-methyl-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using1-(2-Chlorophenyl)-6-methyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.83 (d, J=4.5 Hz, 1H), 8.23 (s, 1H),7.76-7.74 (m, 1H), 7.59-7.56 (m, 2H), 7.53-7.51 (m, 1H), 6.44 (s, 1H),3.01 (d, J=4.5 Hz, 3H), 2.45 (s, 3H). m/z [M+H]⁺ 368.4

1-(2-Chlorophenyl)-7-cyclopropyl-6-methyl-4-(methylamino)quinazolin-2(1H)-one was prepared by using1-(2-Chlorophenyl)-7-cyclopropyl-6-methylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, J=4 Hz, 1H), 7.89 (s, 1H),7.72-7.70 (m, 1H), 7.56-7.52 (m, 2H), 7.41-7.39 (m, 1H), 5.76 (s, 1H),2.97 (d, J=4 Hz, 3H), 2.39 (s, 3H), 1.92-1.88 (m, 1H), 0.88-0.85 (m,2H), 0.23-0.20 (m, 2H). m/z [M+H]⁺ 340.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1-methyl-1H-pyrazol-3-yl)methyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using (1-methyl-1H-pyrazol-3-yl)methanamine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆): δ 9.12 (s, 1H), 8.76 (s, 1H), 7.75-7.72 (m,1H), 7.61 (d, J=2 Hz, 1H), 7.60-7.54 (m, 2H), 7.49-7.47 (m, 1H), 6.23(s, 1H), 5.74 (s, 1H), 4.66 (dd, J=26, 15 Hz, 2H), 3.81 (s, 3H),2.16-2.11 (m, 1H), 1.08-1.06 (m, 2H), 0.42-0.38 (m, 2H), m/z [M+H]⁺431.38.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-3-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using isoxazol-3-ylmethanamine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) (9.29 (s, 1H), 8.88 (d, J=1.5 Hz, 1H), 8.71(s, 1H), 7.76-7.74 (m, 1H), 7.60-7.56 (m, 2H), 7.50-7.48 (m, 1H), 6.63(d, J=1.5 Hz, 1H), 5.77 (s, 1H), 4.83 (dd, J=40.0, 15.5 Hz, 2H),2.15-2.14 (m, 1H), 1.10-1.08 (m, 2H), 0.43-0.42 (m, 2H). m/z [M+H]⁺418.3.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((isoxazol-5-ylmethyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using isoxazol-5-ylmethanamine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆): δ 9.34 (t, J=5.5 Hz, 1H), 8.72 (s, 1H), 8.54(d, J=1.5 Hz, 1H), 7.76-7.74 (m, 1H), 7.60-7.55 (m, 2H), 7.51-7.49 (m,1H), 6.49 (s, 1H), 4.95 (dd, J=16.5, 5.5 Hz, 2H), 4.87 (dd, J=16, 5.5Hz, 1H), 2.17-2.13 (m, 1H), 1.23 (d, J=3.5 Hz, 1H), 1.11-1.07 (m, 2H),0.42-0.41 (m, 2H). m/z [M+H]⁺ 418.35.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((1-methyl-1H-pyrazol-5-yl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using 1-methyl-1H-pyrazol-5-amine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) δ 10.30 (s, 1H), 8.87 (br s, 1H), 7.78 (d, J=7Hz, 1H), 7.60-7.55 (m, 3H), 7.44 (br s, 1H), 6.27 (br s, 1H), 5.77 (t,J=15.5 Hz, 1H), 3.74 (br s, 3H), 2.21-2.16 (m, 1H), 1.13-1.09 (m, 2H),0.5-0.4 (m, 2H). m/z [M+H]⁺ 417.36.

1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-4-(thiazol-5-ylamino)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using thiazol-5-amine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆): δ 11.9 (br s, 1H), 8.75 (s, 1H), 8.59 (s,1H), 7.84 (s, 1H), 7.76-7.73 (m, 1H), 7.60-7.55 (m, 2H), 7.50-7.47 (m,1H), 5.74 (s, 1H), 2.17-2.12 (m, 1H), 1.08-1.07 (m, 2H), 0.45-0.41 (m,2H). m/z [M+H]⁺ 420.1.

1-(2-Chlorophenyl)-7-cyclopropyl-2-oxo-4-((2-(trifluoromethyl)pyridin-4-yl)amino)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using 2-(trifluoromethyl)pyridin-4-amine and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) (10.54 (br s, 1H), 8.92-8.17 (m, 4H),7.79-7.77 (m, 1H), 7.64-7.54 (m, 3H), 5.79 (d, J=13.5 Hz, 1H), 2.22-2.16(m, 1H), 1.13-1.11 (m, 2H), 0.45-0.45 (m, 2H). m/z [M+H]⁺ 482.5.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-hydroxycyclobutyl)amino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrileas a single, unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-Chlorophenyl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.SFC purification (20% MeOH, Chiralpak IC, peak 3).

¹H NMR (500 MHz, DMSO-d₆): δ 8.86 (s, 1H), 8.73 (s, 1H), 7.74-7.72 (m,1H), 7.59-7.54 (m, 2H), 7.47-7.46 (m, 1H), 5.71 (d, J=10 Hz, 1H), 4.44(s, 1H), 4.11 (s, 1H), 2.14-2.12 (m, 1H), 2.08-2.02 (m, 2H), 1.56-1.48(m, 1H), 1.43-1.37 (m, 1H), 1.23 (s, 1H), 1.06 (dd, J=8, 2 Hz, 2H), 0.40(d, J=4.5 Hz, 2H), m/z [M+H]⁺ 407.47.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)-2-oxo-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using1-(2-chloropyridin-3-yl)-7-cyclopropyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carbonitrile.

¹H NMR (500 MHz, DMSO-d₆) δ 8.88 (d, J=4.0 Hz, 1H), 8.63 (s, 1H), 8.59(dd, J=5.0, 1.5 Hz, 1H), 8.04 (dd, J=8.0, 1.5 Hz, 1H), 7.68 (dd, J=7.5,5.0 Hz, 1H), 5.82 (s, 1H), 2.99 (d, J=4.5 Hz, 3H), 2.18-2.13 (m, 1H),1.09 (dd, J=8.0, 2.0 Hz, 2H), 1.54-1.53 (m, 2H). m/z [M+H]⁺ 352.4.

1-(2-chlorophenyl)-4-((trans-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one,single unknown enantiomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione. SFCpurification (20% MeOH, R,R Whelk-01, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H),7.77-7.75 (m, 1H), 7.60-7.52 (m, 3H), 7.27 (d, J=8.0 Hz, 1H), 6.11 (s,1H), 4.92-4.78 (m, 1H), 3.49-3.43 (m, 1H), 1.57-1.48 (m, 1H), 1.35-1.26(m, 1H). m/z [M+H]⁺ 414.3.

1-(2-chlorophenyl)-4-((trans-2-fluorocyclopropyl)amino)-7-(trifluoromethoxy)quinazolin-2(1H)-one,single unknown enantiomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-(trifluoromethoxy)quinazoline-2,4(1H,3H)-dione. SFCpurification (20% MeOH, R,R Whelk-01, peak 2).

¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.26 (d, J=9.0 Hz, 1H),7.77-7.75 (m, 1H), 7.60-7.52 (m, 3H), 7.27 (d, J=8.0 Hz, 1H), 6.11 (s,1H), 4.92-4.78 (m, 1H), 3.49-3.43 (m, 1H), 1.57-1.48 (m, 1H), 1.35-1.26(m, 1H). m/z [M+H]⁺ 414.3.

1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.SFC purification (15% MeOH, Chiralpak IC, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (d, J=7 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd,J=8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J=7 Hz, 1H), 4.55-4.49 (m,1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J=19 Hz, 3H),1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H]⁺ 406.37.

1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.SFC purification (15% MeOH, Chiralpak IC, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (d, J=7 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd,J=8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J=7 Hz, 1H), 4.55-4.49 (m,1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J=19 Hz, 3H),1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H]⁺ 406.37.

1-(2-chlorophenyl)-7-(1,1-difluoroethyl)-4-(((trans)-2-hydroxycyclobutyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.SFC purification (15% MeOH, Chiralpak IC, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.82 (d, J=7 Hz, 1H), 8.38 (d, J=8.5 Hz,1H), 7.76-7.73 (m, 1H), 7.59-7.55 (m, 2H), 7.52-7.45 (m, 1H), 7.43 (dd,J=8.5, 1.5 Hz, 1H), 6.36 (s, 1H), 5.43 (d, J=7 Hz, 1H), 4.55-4.49 (m,1H), 4.20-4.14 (m, 1H), 2.09-2.02 (m, 2H), 1.83 (t, J=19 Hz, 3H),1.57-1.49 (m, 1H), 1.46-1.39 (m, 1H). m/z [M+H]⁺ 406.37.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one was prepared by using(1S,2R)-2-fluorocyclopropan-1-amine and1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.53 (m, 2H), 8.14 (d, J=8.5 Hz, 1H),8.08-8.07 (m, 1H), 7.69-7.66 (m, 1H), 6.84 (dd, J=8.5, 1.5 Hz, 1H), 6.15(d, J=1.5 Hz, 1H), 4.91-4.77 (m, 1H), 3.06-3.05 (m, 1H), 1.91-1.88 (m,1H), 1.38-1.32 (m, 1H), 1.25-1.21 (m, 1H), 0.97-0.95 (m, 2H), 0.68-0.62(m, 2H). m/z [M+H]⁺ 371.3.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one was prepared by using cyclopropylmethanamine and1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (t, J=5.0 Hz, 1H), 8.57-8.56 (m, 1H),8.10 (d, J=8.5 Hz, 1H), 8.03 (dd, J=7.5, 2.0 Hz, 1H), 7.68-7.65 (m, 1H),6.83 (dd, J=8.5, 1.5 Hz, 1H), 6.11 (d, J=1.5 Hz, 1H), 3.41-3.39 (m, 1H),3.31-3.31 (m, 1H), 1.90-1.87 (m, 1H), 1.20-1.85 (m, 1H), 0.96-0.94 (m,2H), 0.66-0.62 (m, 2H), 0.51-0.47 (m, 2H), 0.32-0.29 (m, 2H). m/z [M+H]⁺367.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 1).

¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H),7.74-7.71 (m, 1H), 7.58-7.55 (m, 2H), 7.45 (dd, J=6, 3.5 Hz, 1H), 6.81(dd, J=8.5, 1.5 Hz, 1H), 6.02 (d, J=1 Hz, 1H), 4.90-4.70 (m, 1H),3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m,1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H]⁺ 370.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 2).

¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H),7.74-7.71 (m, 1H), 7.58-7.55 (m, 2H), 7.45 (dd, J=6, 3.5 Hz, 1H), 6.81(dd, J=8.5, 1.5 Hz, 1H), 6.02 (d, J=1 Hz, 1H), 4.90-4.70 (m, 1H),3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m,1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H]⁺ 370.34.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2S)-2-fluorocyclopropyl)amino)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 3).

¹H NMR (500 MHz, DMSO-d₆) δ 8.32 (s, 1H), 7.96 (d, J=8.5 Hz, 1H),7.74-7.71 (m, 1H), 7.58-7.55 (m, 2H), 7.45 (dd, J=6, 3.5 Hz, 1H), 6.81(dd, J=8.5, 1.5 Hz, 1H), 6.02 (d, J=1 Hz, 1H), 4.90-4.70 (m, 1H),3.45-3.41 (m, 1H), 1.83-1.79 (m, 1H), 1.50-1.45 (m, 1H), 1.22-1.18 (m,1H), 0.94-0.92 (m, 2H), 0.60-0.56 (m, 2H). m/z [M+H]⁺ 370.34.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 1).

¹H NMR (500 MHz, DMSO-d₆) (8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H),7.79-7.76 (m, 1H), 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H),3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H]⁺398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 2).

¹H NMR (500 MHz, DMSO-d₆) (8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H),7.79-7.76 (m, 1H), 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H),3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H]⁺398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 3).

¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H),7.79-7.76 (m, 1H), 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H),3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H]⁺398.3.

1-(2-Chlorophenyl)-4-(((1S,2S)-2-fluorocyclopropyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-one,a single unknown enantiomer/atropisomer was prepared by usingtrans-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione. SFCpurification (30% MeOH, R,R Whelk-01, peak 4).

¹H NMR (500 MHz, DMSO-d₆) δ 8.74 (s, 1H), 8.36 (d, J=8.5 Hz, 1H),7.79-7.76 (m, 1H), 7.64-7.55 (m, 4H), 6.45 (s, 1H), 4.95-4.80 (m, 1H),3.52-3.45 (m, 1H), 1.58-1.49 (m, 1H), 1.29-1.22 (m, 1H). m/z [M+H]⁺398.3.

5-Chloro-4-(methyl amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared by using5-chloro-1-(o-tolyl)-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazolin-2(1H)-onewas prepared by usingtrans-2-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.56-8.51 (m, 2H), 7.98 (dd, J=1.5, 2 Hz,1H), 7.67-7.64 (m, 1H), 6.39 (d, J=1.5 Hz, 1H), 3.99 (s, 3H), 2.99 (d,J=5 Hz, 3H), 1.84 (m, 1H), 0.94-0.92 (m, 2H), 0.67-0.64 (m, 2H). m/z[M+H]⁺ 357.37

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-methoxyquinazolin-2(1H)-one wasprepared by using methanol and1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.63 (dd, J=5.0, 2.0 Hz, 1H), 8.13 (dd,J=7.5, 1.5 Hz, 1H), 7.89 (d, J=8.0 Hz, 1H), 7.73-7.71 (m, 1H), 6.90 (dd,J=8.5, 1.5 Hz, 1H), 6.30 (d, J=1.5 Hz, 1H), 4.09 (s, 3H), 1.99-1.94 (m,1H), 1.01-0.97 (m, 2H), 0.73-0.71 (m, 2H). m/z [M+H]⁺ 328.3.

1-(2-Chloropyridin-3-yl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-onewas prepared by using1-(2-chloropyridin-3-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.57 (dd, J=5.0, 2.0 Hz, 2H), 8.03-7.99 (m,2H), 7.68-7.66 (m, 1H), 6.82 (dd, J=8.5, 1.5 Hz, 1H), 6.12 (d, J=1.5 Hz,1H), 2.97 (d, J=4.5 Hz, 3H), 1.89-1.85 (m, 1H), 0.96-0.94 (m, 2H),0.68-0.66 (m, 2H). m/z [M+H]⁺ 327.3.

4-(Methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazolin-2(1H)-onewas prepared by using17-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazoline-2,4(1H,3H)-dione.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((2,2-difluorocyclopropyl)methyl)amino)-5-methoxyquinazolin-2(1H)-onewas prepared by using (2,2-difluorocyclopropyl)methanamine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.59 (t, J=5.5 Hz, 1H), 7.73-7.69 (m, 1H),7.56-7.52 (m, 2H), 7.45-7.42 (m, 1H), 6.42 (d, J=1.0 Hz, 1H), 5.59 (d,J=1.0 Hz, 1H), 4.01 (s, 3H), 3.73-3.66 (m, 2H), 2.26-2.23 (m, 1H),1.80-1.77 (m, 1H), 1.65-1.61 (m, 1H), 1.49-1.45 (m, 1H), 0.94-0.91 (m,2H), 0.62-0.58 (m, 2H). m/z [M+H]⁺ 432.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-5-methoxyquinazolin-2(1H)-onewas prepared by using cyclopropylmethanamine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.48 (s, 1H), 7.71-7.69 (m, 1H), 7.54-7.52(m, 2H), 7.43-7.41 (m, 1H), 6.42 (d, J=1.5 Hz, 1H), 5.58 (d, J=1.5 Hz,1H), 4.01 (s, 3H), 3.31-3.31 (m, 2H), 1.79-1.76 (m, 1H), 1.23-1.20 (m,1H), 0.92 (dd, J=8.0, 2.0 Hz, 2H), 0.61-0.59 (m, 2H), 0.51-0.47 (m, 2H),0.33-0.32 (m, 2H). m/z [M+H]⁺ 396.4.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(((1S,2R)-2-fluorocyclopropyl)amino)-5-methoxyquinazolin-2(1H)-one was prepared by using(1S,2R)-2-fluorocyclopropan-1-amine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.32-8.29 (m, 1H), 7.74-7.70 (m, 1H),7.57-7.53 (m, 2H), 7.47-7.43 (m, 1H), 6.43 (d, J=1.5 Hz, 1H), 5.62 (d,J=1 Hz, 1H), 4.88-4.86 (m, 1H), 3.99 (s, 3H), 3.15-3.12 (m, 1H),1.81-1.78 (m, 1H), 1.27-1.16 (m, 2H), 0.94-0.93 (m, 2H), 0.63-0.60 (m,2H). m/z [M+H]⁺ 400.33.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(cyclopropylamino)-5-methoxyquinazolin-2(1H)-onewas prepared by using cyclopropylamine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.17 (d, J=4.5 Hz, 1H), 7.73-7.69 (m, 1H),7.56-7.52 (m, 2H), 7.44-7.41 (m, 1H), 6.39 (d, J=1 Hz, 1H), 5.58 (d,J=1.5 Hz, 1H), 3.98 (s, 3H), 3.06-3.05 (m, 1H), 1.77 (m, 1H), 0.92 (dd,J=2, 2 Hz, 2H), 0.82 (dd, J=1.5, 1 Hz, 2H), 0.70-0.69 (m, 2H), 0.68-0.59(m, 2H). m/z [M+H]⁺ 382.35.

1-(2-Chlorophenyl)-7-cyclopropyl-4-(isopropylamino)-5-methoxyquinazolin-2(1H)-one was prepared by using isopropylamine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.08 (d, J=7.5 Hz, 1H), 7.71-7.69 (m, 1H),7.54-7.52 (m, 2H), 7.43-7.41 (m, 1H), 6.41 (s, 1H), 5.58 (s, 1H),4.40-4.36 (m, 1H), 4.01 (s, 3H), 1.79-1.76 (m, 1H), 1.28-1.25 (m, 7H),0.93-0.91 (m, 2H), 0.61-0.58 (m, 2H). m/z [M+H]⁺ 384.4.

1-(2-Bromophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one as asingle atropisomer was prepared by using isopropylamine and1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazoline-2,4(1H,3H)-dione.SFC purification (30% MeOH, Chiralpak IG-3, peak 2).

¹H NMR (500 MHz, DMSO-d6) δ 8.48-8.49 (br m, 1H), 7.97 (d, J=8.5 Hz,1H), 7.87 (dd, J=8.0, 1.0 Hz, 1H), 7.59 (td, J=7.5, 1.0 Hz, 1H),7.42-7.48 (m, 2H), 6.81 (dd, J=8.5, 1.5 Hz, 1H), 5.99 (d, J=1.5 Hz, 1H),2.97 (d, J=4.5 Hz, 3H), 1.77-1.99 (m, 1H), 0.90-0.96 (m, 2H), 0.58-0.63(m, 2H). m/z [M+H] 370.3.

4-((trans-2-Hydroxycyclobutyl) amino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared by using trans-2-aminocyclobutan-1-oland 1-phenyl-7-(trifluoromethyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 8.89-8.88 (m, 1H), 8.46 (d, J=8.5 Hz, 1H),7.62-7.52 (m, 4H), 7.35-7.33 (m, 2H), 7.44-7.41 (m, 1H), 6.55 (s, 1H),5.44 (d, J=7 Hz, 1H), 4.5-4.47 (m, 1H), 4.2-4.13 (m, 1H), 2.09-2.02 (m,2H), 1.58-1.50 (m, 1H), 1.47-1.39 (m, 1H). m/z [M+H]⁺ 376.36.

4-Amino-7-cyclopropyl-1-(pyrimidin-5-yl)quinazolin-2(1H)-one wasprepared by using ammonia (7.4 M in THF) and7-cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.87 (s, 2H), 8.13 (s, 1H),8.02 (d, J=8.5 Hz, 2H), 6.83 (dd, J=8.5, 1.5 Hz, 1H), 6.30 (s, 1H),1.92-1.88 (m, 1H), 0.97-0.93 (m, 2H), 0.68-0.65 (m, 2H). m/z [M+H]⁺280.26.

4-Amino-7-cyclopropyl-1-(pyrazin-2-yl)quinazolin-2(1H)-one was preparedby using ammonia (0.4 M in THF) and7-cyclopropyl-1-(pyrazin-2-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (8.78 (s, 3H), 8.15 (s, 1H), 8.02 (d, J=8.5Hz, 2H), 6.82 (dd, J=8.5, 1.5 Hz, 1H), 6.21 (d, J=1.5 Hz, 1H), 1.89-1.84(m, 1H), 0.96-0.92 (m, 2H), 0.66-0.65 (m, 2H). m/z [M+H]⁺ 280.4.

4-Amino-1-(3-chloropyridin-2-yl)-7-cyclopropylquinazolin-2(1H)-one wasprepared by using ammonia (0.4 M in THF) and1-(3-chloropyridin-2-yl)-7-cyclopropylquinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (8.65 (dd, J=4.5, 1.2 Hz, 1H), 8.25 (dd,J=8.5, 2.0 Hz, 1H), 8.13 (s, 1H), 8.03 (d, J=8.5 Hz, 1H), 7.98 (s, 1H),7.65-7.63 (m, 1H), 6.81 (dd, J=8.5, 1.5 Hz, 1H), 6.00 (d, J=1.5 Hz, 1H),1.87-1.82 (m, 1H), 0.96-0.93 (m, 2H), 0.66-0.62 (m, 2H). m/z [M+H]⁺313.3.

7-Cyclopropyl-4-(methylamino)-1-(pyrimidin-5-yl)quinazolin-2(1H)-one wasprepared by using7-cyclopropyl-1-(pyrimidin-5-yl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.30 (s, 1H), 8.86 (s, 1H), 8.57 (d, J=4.5,1H), 7.98 (d, J=10, 1H), 6.83 (dd, J=8.5, 1.5 Hz, 1H), 6.30 (s, 1H),2.97 (d, J=4.5, 3H), 1.92-1.87 (m, 1H), 0.96-0.92 (m, 2H), 0.68-0.65 (m,2H). m/z [M+H]⁺ 294.33.

7-Cyclopropyl-4-(methylamino)-1-(pyrazin-2-yl)quinazolin-2(1H)-one wasprepared by using4-chloro-7-cyclopropyl-1-(pyrazin-2-yl)quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) (8.79-8.78 (m, 3H), 8.60 (d, J=4.5 Hz, 1H),7.99 (d, J=8.5 Hz, 1H), 6.84 (dd, J=8.5, 1.5 Hz, 1H), 6.21 (d, J=1.5 Hz,1H), 2.98 (d, J=4.5 Hz, 3H), 1.89-1.83 (m, 1H), 0.95-0.92 (m, 2H),0.66-0.63 (m, 2H). m/z [M+H]⁺ 294.4.

1-(2-Chlorophenyl)-4-(((1-methyl-1H-imidazol-4-yl)methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using (1-methyl-1H-imidazol-4-yl)methanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) (9.36 (t, J=5 Hz, 1H), 8.93 (d, J=8 Hz, 1H),7.76 (d, J=8.5 Hz, 1H), 7.64-7.62 (m, 1H), 7.54 (s, 1H), 7.48-7.43 (m,3H), 7.1 (s, 1H), 4.60 (t, J=5 Hz, 2H), 3.62 (s, 1H). m/z [M+H]⁺ 435.27.

1-(2-Chlorophenyl)-4-(((1-methyl-1H-pyrazol-5-yl)methyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using (1-methyl-1H-pyrazol-5-yl)methanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆): δ 9.43 (t, J=5 Hz, 1H), 8.91 (d, J=8 Hz, 1H),7.80 (d, J=8 Hz, 1H), 7.63 (m, 1H), 7.50-7.44 (m, 3H), 7.36 (d, J=1.5Hz, 1H), 6.29 (d, J=2 Hz, 1H), 4.87-4.74 (m, 2H), 3.90 (s, 3H). m/z[M+H]+: 435.27.

1-(2-Chlorophenyl)-4-((isoxazol-5-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by usingisoxazol-5-ylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.66 (t, J=5.5 Hz, 1H), 8.89 (d, J=3.0 Hz,1H), 8.55 (d, J=1.5 Hz, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.66-7.63 (m, 1H),7.50-7.46 (m, 3H), 6.52 (d, J=2.0 Hz, 1H), 5.01-4.89 (m, 2H). m/z [M+H]⁺422.2.

1-(2-Chlorophenyl)-4-((isoxazol-3-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by usingisoxazol-3-ylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.62 (t, J=5.5 Hz, 1H), 8.91-8.88 (m, 2H),7.83 (d, J=8.5 Hz, 1H), 7.66-7.63 (m, 1H), 7.50-7.45 (m, 3H), 6.66 (d,J=2.0 Hz, 1H), 4.93-4.81 (m, 2H). m/z [M+H]⁺ 422.3.

1-(2-Chlorophenyl)-4-((isoxazol-4-ylmethyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by usingisoxazol-4-ylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.41 (s, 1H), 8.98 (s, 1H), 8.86 (d, J=8.0Hz, 1H), 8.68 (s, 1H), 7.82 (d, J=8.0 Hz, 1H), 7.65-7.63 (m, 1H),7.50-7.44 (m, 3H), 4.65 (dd, J=40.0, 15.0 Hz, 2H). m/z [M+H]⁺ 422.3.

1-(2-Chlorophenyl)-4-(thiazol-4-ylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by usingisoxazol-3-ylmethanamine and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 11.8 (s, 1H), 9.12 (s, 1H), 8.93 (d, J=8.0Hz, 1H), 7.79 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 7.62-7.60 (m, 1H),7.51-7.46 (m, 3H). m/z [M+H]⁺ 424.2.

7-Cyclopropyl-4-(pyridin-4-ylamino)-1-(o-tolyl)quinazolin-2(1H)-one wasprepared by using pyridin-4-amine and7-cyclopropyl-1-(o-tolyl)quinazoline-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d₆) δ 9.97 (s, 1H), 8.52 (d, J=6.5 Hz, 2H), 8.38(d, 8.5 Hz, 1H), 8.04 (dd, 4.5 Hz, 1.5 Hz, 2H), 7.49-7.41 (m, 3H), 7.23(dd, 7.5, 1.5 Hz, 1H), 6.95 (dd, 8.5, 1.5 Hz, 1H), 6.10 (s, 1H), 1.96(s, 3H), 1.86-1.82 (m, 1H), 0.98-0.96 (m, 2H), 0.64-0.63 (m, 2H). m/z[M+H]⁺ 369.39.

4-(Methylamino)-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-onewas prepared by using4-chloro-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

7-Cyclopropyl-4-(methylamino)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-onewas prepared by using7-cyclopropyl-4-hydroxy-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

4-Amino-7-cyclopropyl-5-methoxy-1-(pyridin-3-yl) quinazolin-2(1H)-onewas prepared by using ammonia (2 M in THF) and4-chloro-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.66 (d, J=4 Hz, 1H), 8.46-8.45 (m, 1H),8.03 (s, 1H), 7.88 (s, 1H), 7.77-7.75 (m, 1H), 7.62-7.59 (m, 1H), 6.38(s, 1H), 5.67 (s, 1H), 3.97 (s, 3H), 1.83-1.78 (m, 1H), 0.95-0.90 (m,2H), 0.64 (m, 2H). m/z [M+H]⁺ 309.36.

7-Cyclopropyl-5-methoxy-4-(methylamino)-1-(pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using4-chloro-1-(2-chloropyridin-3-yl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.68-8.67 (m, 1H), 8.47-8.45 (m, 2H),7.77-7.75 (m, 1H), 7.62-7.59 (m, 1H), 6.40 (d, J=1.5 Hz, 1H), 5.67 (d,J=1 Hz, 1H), 3.98 (s, 3H), 2.98 (d, J=4.5 Hz, 3H), 1.81-1.78 (m, 1H),0.93-0.90 (m, 2H), 0.62-0.61 (m, 2H). m/z [M+H]⁺ 323.36.

4-Amino-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one wasprepared by using ammonia (2 M in THF) and4-chloro-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) (8.54 (s, 1H), 7.90 (s, 1H), 7.80 (s, 1H),7.43-7.34 (m, 3H), 7.12-7.10 (m, 1H), 6.36 (s, 1H), 5.56 (s, 1H), 3.96(s, 3H), 1.92 (s, 3H), 1.76-1.71 (m, 1H), 0.91-0.89 (m, 2H), 0.57-0.56(m, 2H). m/z [M+H]⁺ 322.36.

7-Cyclopropyl-5-methoxy-4-(methylamino)-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using4-chloro-7-cyclopropyl-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) (8.39 (d, J=4.4 Hz, 1H), 7.44-7.34 (m, 3H),7.11-7.09 (m, 2H), 6.38 (s, 1H), 5.56 (d, J=0.8 Hz, 1H), 3.98 (s, 3H),2.98 (d, J=4.8 Hz, 3H), 1.91 (s, 3H), 1.76-1.69 (m, 1H), 0.91-0.88 (m,2H), 0.57-0.54 (m, 2H). m/z [M+H]⁺ 336.44.

4-Amino-1-(2-chlorophenyl)-7-cyclopropyl-5-methoxyquinazolin-2(1H)-onewas prepared by using ammonia (2 M in THF) and1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 8.0 (s, 1H), 7.86 (s, 1H), 7.71-7.68 (m,1H), 7.55-7.51 (m, 2H), 7.43-7.40 (m, 1H), 6.37 (d, J=1.5 Hz, 1H), 5.57(s, 1H), 3.97 (s, 3H), 1.80-1.75 (m, 1H), 0.93-0.90 (m, 2H), 0.64-0.63(m, 1H). m/z [M+H]⁺ 342.31.

1-(2-Chlorophenyl)-7-cyclopropyl-5-methoxy-4-(methylamino)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-cyclopropyl-4-hydroxy-5-methoxyquinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.45 (d, 1H), 7.71-7.69 (m, 1H), 7.54-7.52(m, 2H), 7.41-7.39 (m, 1H), 6.39 (s, 1H), 5.57 (d, J=1 Hz, 1H), 3.98 (s,3H), 2.98 (d, J=4.5 Hz, 3H), 1.78-1.74 (m, 1H), 0.92-0.90 (m, 2H), 0.59(m, 2H). m/z [M+H]⁺ 356.35.

4-Amino-1-(2-Bromophenyl)-7-cyclopropylquinazolin-2(1H)-one was preparedby using ammonia (2 M in THF) and1-(2-Bromophenyl)-7-cyclopropyl-4-hydroxyquinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.01-7.99 (m, 2H), 7.89-7.85 (m, 2H),7.60-7.58 (m, 1H), 7.47-7.42 (m, 2H), 6.79 (dd, J=8.5, 1.5 Hz, 1H), 5.98(d, J=1.5 Hz, 1H), 1.82-1.78 (m, 1H), 0.94-0.90 (m, 2H), 0.62-0.57 (m,2H). m/z [M+H]⁺ 356.1.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onea single unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.SFC purification (20% MeOH, Chiralpak IC, peak 1).

¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.83 (s, 1H), 7.72-7.71 (m,1H), 7.67-7.60 (m, 1H), 7.46-7.41 (m, 3H), 5.67 (s, 1H), 4.37 (d, J=5.0Hz, 1H), 4.07 (s, 1H), 2.06 (dd, J=17.0, 8.5 Hz, 2H), 1.56-1.42 (m, 2H).m/z [M+H]⁺ 411.3.

1-(2-Chlorophenyl)-4-(((trans)-2-hydroxycyclobutyl)amino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onea single unknown enantiomer/atropisomer was prepared by usingtrans-2-aminocyclobutan-1-ol and1-(2-chlorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.SFC purification (20% MeOH, Chiralpak IC, peak 2).

¹H NMR (400 MHz, DMSO-d₆) δ 9.15 (s, 1H), 8.83 (s, 1H), 7.72-7.71 (m,1H), 7.67-7.60 (m, 1H), 7.46-7.41 (m, 3H), 5.67 (s, 1H), 4.37 (d, J=5.0Hz, 1H), 4.07 (s, 1H), 2.06 (dd, J=17.0, 8.5 Hz, 2H), 1.56-1.42 (m, 2H).m/z [M+H]⁺ 411.3.

7-Chloro-1-(2-chlorophenyl)-5-fluoro-4-(methylamino)quinazolin-2(1H)-onewas prepared by using4,7-dichloro-1-(2-chlorophenyl)-5-fluoroquinazolin-2(1H)-one.

7-Chloro-5-fluoro-4-(((trans)-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using (trans)-3-methoxycyclobutan-1-amine and7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

7-Chloro-4-((2,2-difluoroethyl)amino)-5-fluoro-1-(o-tolyl)quinazolin-2(1H)onewas prepared by using 2,2-difluoroethan-1-amine and7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

4-Amino-7-chloro-5-fluoro-1-(o-tolyl)quinazolin-2(1H)-one was preparedby using ammonia (0.4 M in THF) and7-chloro-5-fluoro-4-hydroxy-1-(o-tolyl)quinazolin-2(1H)-one.

1-Benzyl-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-onewas prepared by using1-benzyl-4-hydroxy-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) (8.89 (d, J=4.5 Hz, 1H), 8.71 (d, J=8.0 Hz,1H), 7.76 (d, J=8.5 Hz, 1H), 7.35-7.33 (m, 2H), 7.28-7.25 (m, 1H),7.22-7.19 (m, 1H), 5.35 (s, 2H), 2.97 (d, J=4.5 Hz, 3H). m/z [M+H]⁺335.3.

1-(2-Chlorophenyl)-4-(3-hydroxy-3-methylpyrrolidin-1-yl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one a single unknown enantiomer wasprepared by using 3-methylpyrrolidin-3-ol and1-(2-chlorophenyl)-7-(1,1-difluoroethyl)quinazoline-2,4(1H,3H)-dione.SFC purification (25% MeOH, Chiralpak IC, peak 1).

¹H NMR (400 MHz, DMSO-d₆) δ 8.88-8.76 (m, 1H), 7.64-7.63 (m, 2H),7.48-7.45 (m, 2H), 7.42-7.39 (m, 1H), 5.03 (s, 1H), 4.30-3.64 (m, 4H),2.07-1.94 (m, 2H), 1.40 (s, 3H). m/z [M+H]⁺ 425.1.

7-Cyclopropyl-4-(methylamino)-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-onewas prepared by using7-Cyclopropyl-4-hydroxy-1-(2-methylpyridin-3-yl)quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.58-8.57 (dd, J=4.5, 1.5 Hz, 1H), 8.51 (d,J=4 Hz, 1H), 8.0 (d, J=8.5 Hz, 1H), 7.66-7.65 (dd, J=8, 1.5 Hz, 1H),7.45-7.43 (dd, J=7.5, 4.7 Hz, 1H), 6.83-6.81 (dd, J=8.5, 1.5 Hz, 1H),6.03 (s, 1H), 2.97 (d, J=4.5 Hz, 3H), 2.13 (s, 3H), 1.85-1.80 (m, 1H),0.94-0.90 (m, 2H), 0.64-0.59 (m, 2H). m/z [M+H]⁺ 307.22.

1-(2-Chloro-6-fluorophenyl)-4-(methylamino)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by using4-chloro-1-(2-chloro-6-fluorophenyl)-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 9.26 (d, J=4.5 Hz, 1H), 8.84 (d, J=8.0 Hz,1H), 7.87 (d, J=8.0 Hz, 1H), 7.59-7.52 (m, 2H), 7.46-7.43 (m, 1H), 3.04(d, J=4.5 Hz, 3H). m/z [M+H]⁺ 373.2.

5-Methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidin-2(1H)-one was prepared by using5-methoxy-1-phenyl-7-(trifluoromethyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione.

¹H NMR (500 MHz, DMSO-d6) δ 8.56 (d, J=5.0 Hz, 1H), 7.62-7.59 (m, 2H),7.55-7.52 (m, 1H), 7.35-7.33 (m, 2H), 6.22 (s, 1H), 4.11 (s, 3H), 3.03(d, J=5.0 Hz, 3H). m/z [M+H]⁺ 351.3.

Example 3 Synthesis of7-methyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one

A vial was charged with7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv),methylboronic acid (3 equiv) and 1,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (0.1 equiv). A 1:1 mixture of toluene:t-butanol(0.1 M) was added followed by aqueous potassium carbonate (2 M, 4equiv). The reaction mixture was heated to 100° C. for 2 h and thencooled. The crude reaction mixture was diluted with ethyl acetate,filtered and concentrated under reduced pressure. The residue waspurified by preparatory HPLC (20-40% MeCN/water, 0.1% formic acid) togive the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.81 (d, J=8.3 Hz,1H), 7.52 (t, J=7.5 Hz, 2H), 7.45 (t, J=7.2 Hz, 1H), 7.24 (s, 3H), 6.95(d, J=8.2 Hz, 1H), 6.30 (s, 1H), 3.18 (s, 3H), 2.23 (s, 3H). m/z [M+H]⁺266.1

Proceeding analogously as described above the following compounds wereprepared:

7-Cyclopropyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one was preparedby substituting cyclopropyl boronic acid for methylboronic acid

¹H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=8.4 Hz, 1H), 7.52 (t, J=7.4 Hz,2H), 7.48-7.40 (m, 1H), 7.24 (s, 2H), 6.71 (d, J=8.3 Hz, 1H), 6.23 (s,1H), 3.15 (s, 3H), 1.77-1.66 (m, 1H), 0.94 (d, J=7.8 Hz, 2H), 0.58 (d,J=4.9 Hz, 2H). m/z [M+H]⁺ 292.2

4-(Dimethylamino)-7-(oxetan-3-yl)-1-phenylquinazolin-2(1H)-one wasprepared by substituting potassium trifluoro(oxetan-3-yl) borate formethyl boronic acid and7-bromo-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one for7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

¹H NMR (400 MHz, Chloroform-d) δ 7.80 (d, J=8.5 Hz, 1H), 7.56 (t, J=7.4Hz, 2H), 7.51-7.44 (m, 1H), 7.28 (d, J=7.7 Hz, 3H), 7.17 (d, J=8.5 Hz,1H), 6.46 (d, J=11.3 Hz, 2H), 6.30 (dt, J=15.4, 4.8 Hz, 1H), 4.28 (d,J=4.8 Hz, 2H), 3.41 (s, 6H). m/z [M+H]⁺ 322.0

4-(Dimethylamino)-1-phenyl-7-(tetrahydrofuran-3-yl)quinazolin-2(1H)-onewas prepared by substituting potassium tetrahydrofuran-3-trifluoroboratefor methyl boronic acid and7-bromo-4-(dimethylamino)-1-phenylquinazolin-2(1H)-one for7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

¹H NMR (400 MHz, Chloroform-d) δ 7.79 (d, J=8.6 Hz, 1H), 7.56 (t, J=7.4Hz, 2H), 7.49 (q, J=7.1, 6.2 Hz, 1H), 7.29 (d, J=7.9 Hz, 3H), 7.18 (d,J=8.4 Hz, 1H), 6.43 (s, 1H), 6.33 (d, J=17.6 Hz, 1H), 6.22 (dt, J=15.6,6.9 Hz, 1H), 3.73 (t, J=6.0 Hz, 2H), 3.43 (s, 6H), 2.44 (q, J=6.6, 6.1Hz, 2H). m/z [M+H]⁺ 336.0

7-Ethyl-4-(methylamino)-1-phenylquinazolin-2(1H)-one was prepared bysubstituting ethyl boronic acid for methyl boronic acid.

¹H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J=8.3 Hz, 1H), 7.56 (t, J=7.7Hz, 2H), 7.49 (t, J=7.5 Hz, 1H), 7.29 (d, J=8.0 Hz, 2H), 7.04 (d, J=8.3Hz, 1H), 6.35 (s, 1H), 3.24 (s, 3H), 2.54 (q, J=7.7 Hz, 2H), 1.11 (t,J=7.6 Hz, 3H). m/z [M+H]⁺ 280.1.

6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-onewas prepared by using cyclopropylboronic acid for methyl bornonic acidand7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-onefor 7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 8.72 (s, 1H), 8.41 (s, 1H), 7.73 (d, J=6.6Hz, 1H), 7.65-7.53 (m, 2H), 7.53-7.41 (m, 1H), 5.75 (d, J=2.0 Hz, 1H),2.12 (br s, 1H), 1.19 (s, 1H), 0.99 (d, J=8.3 Hz, 2H), 0.51 (d, J=7.8Hz, 2H), 0.40-0.21 (m, 4H). m/z [M+H]⁺ 400.1

6-Chloro-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-onewas prepared by using cyclopropylboronic acid and7-bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO) δ 8.67 (br s, 1H), 8.28 (s, 1H), 7.75 (m, 1H),7.65-7.55 (m, 2H), 7.46 (m, 1H), 5.76 (s, 1H), 2.98 (s, 3H), 2.12 (s,1H), 0.98 (d, J=8.2 Hz, 2H), 0.28 (s, 2H). m/z [M+H]⁺ 360.0.

4-((Cyclopropylmethyl)amino)-6-methyl-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using6-bromo-4-((cyclopropylmethyl)amino)-1-phenyl-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹H NMR (400 MHz, MeOD) δ 8.15 (s, 1H), 7.61 (m, 3H), 7.33 (d, J=7.8 Hz,2H), 6.38 (s, 1H), 3.52 (d, J=8.3 Hz, 2H), 2.37 (s, 3H), 1.30 (m, 2H),0.59 (d, J=7.8 Hz, 2H), 0.39 (br s, 2H). m/z [M+H]⁺ 390.1.

6-Methyl-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using6-bromo-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹H NMR (400 MHz, MeOD) δ 8.04 (s, 1H), 7.58-7.37 (m, 3H), 7.22 (d, J=7.5Hz, 1H), 6.27 (s, 1H), 3.15 (s, 3H), 2.37 (s, 3H), 2.05 (s, 3H). m/z[M+H]⁺ 364.1.

4-((Cyclopropylmethyl)amino)-6-methyl-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-onewas prepared by using6-bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹H NMR (400 MHz, MeOD) δ 8.18 (s, 1H), 7.59-7.39 (m, 3H), 7.22 (d, J=7.5Hz, 1H), 6.27 (s, 1H), 3.52 (appar t, J=6.9 Hz, 2H), 2.38 (s, 3H), 2.05(s, 3H), 1.31 (s, 1H), 0.60 (d, J=7.8 Hz, 2H), 0.39 (br s, 2H). m/z[M+H]⁺ 404.1

1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-fluoroquinazolin-2(1H)-onewas prepared by using cyclopropylboronic acid and7-bromo-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-6-fluoroquinazolin-2(1H)-one.

1-(2-chlorophenyl)-7-cyclopropyl-6-fluoro-4-(methylamino)quinazolin-2(1H)-onewas prepared by substituting cyclopropyl boronic acid and using7-bromo-1-(2-chlorophenyl)-6-fluoro-4-(methylamino)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d6) δ 8.56 (s, 1H), 7.97 (d, J=11.0 Hz, 1H),7.76-7.69 (m, 1H), 7.55 (d, J=6.7 Hz, 2H), 7.44 (d, J=3.0 Hz, 1H), 5.75(d, J=5.4 Hz, 1H), 2.97 (s, 3H), 2.05-1.93 (m, 1H), 0.95 (d, J=8.4 Hz,2H), 0.40 (t, J=5.2 Hz, 2H). m/z [M+H]⁺ 344.0.

Example 4 Synthesis of7-chloro-1-(3-hydroxyphenyl)-4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one

Step 1: 3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenylacetate

A vial was charged with7-chloro-1-(3-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione (1.0 equiv) andPyridine (0.6 M). To the reaction vessel was added acetic anhydride (1.2equiv) and the reaction mixture was stirred to reflux for 60 minutes.The reaction was concentrated under vacuum, and the crude reactionmixture was purified by normal phase purification (0-20% MeOH/DCM) togive the title compound. m/z [M+H]⁺ 331.1

3-(7-Chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenyl acetate wasconverted to 3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenylacetate by following the procedure in Examples 1 and 2.

Step 2:7-chloro-1-(3-hydroxyphenyl)-4-(methylamino)-3,4-dihydroquinazolin-2(1H)-one

A vial was charged with crude3-(7-chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl acetate (1.0equiv) THF:MeOH (3:2 ratio 0.6 M) was added followed by addition of 2Naqueous solution of LiOH (10 equiv). The reaction vessel was was stirredat room temperature for 30 min. The reaction was concentrated undervacuum, and the crude reaction mixture was purified by reverse phasepurification (20-55% MeCN/water, 0.1% formic acid) to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 10.2 (bs, 1H), 8.63 (d, J=5.1 Hz,1H), 8.10 (d, J=8.7 Hz, 1H), 7.37 (t, J=8.0 Hz, 1H), 7.27 (d, J=8.5 Hz,1H), 6.91 (d, J=8.4 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H), 6.64 (s, 1H), 6.38(s, 1H), 2.97 (d, J=4.2 Hz, 4H). m/z [M+H]⁺ 302.1.

Proceeding analogously as described above, following compounds wereprepared by substituting for7-chloro-1-(3-hydroxyphenyl)quinazoline-2,4(1H,3H)-dione and methylamineas needed:

7-Chloro-1-[3-(2-hydroxyethyl)phenyl]-4-(methylamino)hydroquinazolin-2-onewas prepared by using3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenethyl acetate

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=5.0 Hz, 1H), 8.10 (d, J=8.6 Hz,1H), 7.49 (t, J=7.6 Hz, 1H), 7.37 (d, J=7.7 Hz, 1H), 7.27 (d, J=8.6 Hz,1H), 7.11 (d, J=7.9 Hz, 2H), 6.34 (d, J=2.0 Hz, 1H), 4.69 (t, J=5.3 Hz,1H), 3.66 (d, J=6.7 Hz, 2H), 2.98 (d, J=4.3 Hz, 3H), 2.81 (t, J=6.9 Hz,2H). m/z [M+H]⁺ 330.1

7-Chloro-1-[3-(3-hydroxypropyl)phenyl]-4-(methylamino)hydroquinazolin-2-onewas prepared by using3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenpropyl acetate

¹H NMR (400 MHz, DMSO-d₆) δ 8.61 (d, J=5.2 Hz, 1H), 8.11 (d, J=8.6 Hz,1H), 7.50 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.28 (d, J=8.7 Hz,1H), 7.12 (s, 2H), 6.31 (s, 1H), 4.49 (t, J=5.2 Hz, 1H), 3.45 (d, J=6.1Hz, 3H), 2.98 (d, J=4.3 Hz, 3H), 2.70 (t, J=7.8 Hz, 2H), 1.76 (p, J=6.9Hz, 3H). 11.81 (s, 1H), 8.04 (d, J=8.5 Hz, 1H), 7.52 (t, J=7.6 Hz, 1H),7.39 (d, J=7.8 Hz, 1H), 7.31 (dd, J=8.4, 1.8 Hz, 1H), 7.29-7.22 (m, 2H),2.40 (s, 3H). m/z [M+H]⁺ 344.1

4-(dimethylamino)-7-chloro-1-(3-hydroxyphenyl)hydroquinazolin-2-one wasprepared by using3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenyl acetate anddimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 9.87 (s, 1H), 8.03 (dd, J=8.7, 1.4 Hz, 1H),7.38 (t, J=8.0 Hz, 1H), 7.23-7.14 (m, 1H), 6.92 (d, J=8.3 Hz, 1H), 6.69(d, J=7.8 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.41 (d, J=2.4 Hz, 1H),3.32-3.27 (m, 7H). m/z [M+H]⁺ 316.1

4-(dimethylamino)-7-chloro-1-[3-(hydroxymethyl)phenyl]hydroquinazolin-2-onewas prepared by using3-(7-chloro-2,4-dioxo-3,4-dihydroquinazolin-1(2H)-yl)phenmethyl acetateand dimethylamine

¹H NMR (400 MHz, DMSO-d₆) δ 8.05 (d, J=8.8 Hz, 1H), 7.55 (t, J=7.6 Hz,1H), 7.46 (d, J=7.9 Hz, 1H), 7.22 (s, 1H), 7.20-7.14 (m, 2H), 6.35 (s,1H), 5.35 (s, 1H), 4.59 (s, 2H), 3.31 (s, 11H). m/z [M+H]⁺ 330.0

Example 5 Synthesis of7-methoxy-4-(methylamino)-1-phenylquinazolin-2(1H)-one

To a vial charged with7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv) andcopper iodide (2 equiv). DMF (0.1 M) was added sodium methoxide (10equiv). The reaction mixture was heated to 100° C. for 2 hours and thencooled. The crude reaction mixture was diluted with ethyl acetate,filtered and concentrated under reduced pressure. The residue waspurified by preparatory HPLC (10-30% MeCN/water, 0.1% formic acid) togive the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J=9.0 Hz,1H), 7.54 (t, J=7.6 Hz, 2H), 7.51-7.43 (m, 1H), 7.28 (d, J=7.7 Hz, 2H),6.74 (d, J=9.0 Hz, 1H), 5.95 (s, 1H), 3.66 (s, 3H), 3.20 (s, 3H). m/z[M+H]⁺ 282.1

Proceeding analogously as described above1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-methoxyquinazolin-2(1H)-onewas prepared by using6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 7.71 (s, 1H), 7.65 (s, 1H),7.53 (d, J=3.7 Hz, 2H), 7.41 (d, J=6.7 Hz, 1H), 5.64 (s, 1H), 3.90 (s,3H), 3.42 (dd, J=12.8, 6.9 Hz, 2H), 2.12-2.05 (m, 1H), 1.26-1.19 (m,1H), 0.88 (d, J=8.4 Hz, 2H), 0.51 (d, J=9.1 Hz, 2H), 0.32 (d, J=4.0 Hz,2H), 0.27-0.20 (m, 2H). m/z [M+H]⁺ 396.2.

Example 6 Synthesis of4-(methylamino)-2-oxo-1-phenyl-1,2-dihydroquinazoline-7-carbonitrile

A vial was charged with7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv),tetrakis(triphenylphosphine)palladium (0.1 equiv) and zinc cyanide (0.5equiv). DMF (0.1 M) was added and the reaction mixture was heated to100° C. for 12 h. Additional zinc cyanide (0.5 equiv) was added and thereaction mixture was heated to 100° C. for additional 24 h. The reactionmixture was cooled and diluted with saturated sodium bicarbonatesolution, and extracted with dichloromethane. The organic layer wasdried over sodium sulfate, filtered and concentrated under reducedpressure. The residue was purified by preparatory HPLC (10-30%MeCN/water, 0.1% formic acid) to give the title compound. ¹H NMR (400MHz, CD₃OD) δ 8.15 (d, J=8.4 Hz, 1H), 7.67 (t, J=7.7 Hz, 2H), 7.61 (d,J=7.0 Hz, 1H), 7.55 (d, J=8.2 Hz, 1H), 7.35 (d, J=7.7 Hz, 2H), 6.82 (s,1H), 3.15 (s, 3H). m z [M+H]⁺ 277.0

Proceeding analogously as described above4-((cyclopropylmethyl)amino)-2-oxo-1-(o-tolyl)-7-(trifluoromethoxy)-1,2-dihydroquinazoline-6-carbonitrilewas prepared by using6-Bromo-4-((cyclopropylmethyl)amino)-1-(o-tolyl)-7-(trifluoromethoxy)quinazolin-2(1H)-one.

¹H NMR (400 MHz, MeOD) δ 8.78 (s, 1H), 7.58-7.40 (m, 3H), 7.25 (d, J=7.7Hz, 1H), 6.40 (s, 1H), 3.52 (m, 2H), 2.07 (s, 3H), 1.29 (br s, 1H), 0.62(d, J=7.7 Hz, 2H), 0.40 (br s, 2H). m/z [M+H]⁺ 415.1.

Example 7 Synthesis of4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one

A vial was charged with7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one (1 equiv), methyl2,2-difluoro-2-(fluorosulfonyl)acetate (2 equiv). Copper iodide (2equiv). DMF (0.1 M) was added and the reaction mixture was heated to100° C. for 12 h. Additional methyl2,2-difluoro-2-(fluorosulfonyl)acetate (2 equiv) and copper iodide (2equiv) were added and the reaction mixture was heated to 100° C. foradditional 24 h. The reaction mixture was cooled, diluted with ethylacetate, filtered and concentrated under reduced pressure. The residuewas purified by preparatory HPLC (10-30% MeCN/water, 0.1% formic acid)to give the title compound. ¹H NMR (400 MHz, CDCl₃) δ 7.76 (d, J=8.7 Hz,1H), 7.59 (t, J=7.4 Hz, 2H), 7.52 (d, J=7.0 Hz, 1H), 7.36 (d, J=9.0 Hz,1H), 7.29 (d, J=7.6 Hz, 2H), 6.81 (s, 1H), 3.27 (s, 3H). m/z [M+H]⁺320.0

Proceeding analogously as described above the following compounds wereprepared by substituting for7-bromo-4-(methylamino)-1-phenylquinazolin-2(1H)-one as needed:

6-chloro-1-(2-chlorophenyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using7-bromo-6-chloro-1-(2-chlorophenyl)-4-(methylamino)quinazolin-2(1H)-one

¹H NMR (400 MHz, DMSO) δ 8.99 (br s, 1H), 8.58 (s, 1H), 7.77 (br s, 1H),7.67-7.52 (m, 3H), 6.54 (s, 1H), 3.02 (s, 3H). m/z [M+H]⁺ 388.0

6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using7-bromo-6-chloro-1-(2-chlorophenyl)-4-((cyclopropylmethyl)amino)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO) δ 9.03 (br, 1H), 8.71 (s, 1H), 7.76 (br, 1H),7.59 (br, 3H), 6.53 (s, 1H), 3.43 (d, J=5.8 Hz, 2H), 1.21 (br s, 1H),0.54 (d, J=7.8 Hz, 2H), 0.33 (br s, 2H). m/z [M+H]⁺ 428.0 Example 8

Synthesis of 4-amino-7-chloro-1-cyclohexylquinazolin-2(1H)-one

Step 1: Synthesis of 4-chloro-2-(cyclohexylamino)benzonitrile

A microwave vial was charged under nitrogen with2-bromo-4-chlorobenzonitrile (1.0 equiv), Pd(OAc)₂ (0.05 equiv), DPPF(0.1 equiv), cyclohexylamine (2.8 equiv) and toluene (0.4 M). Thereaction vessel was sealed, purged with nitrogen for 10 min andsubmitted to microwave irradiation for 30 minutes at 120° C. Thereaction vessel was diluted with 15 mL EtOAc and 5 mL of water. Thelayers were extracted twice with ethyl acetate (2×5 mL). The combinedorganic fractions were dried, and the crude mixture was purified bynormal phase purification (0-70% EtOAc/Hex). m/z [M+H]⁺ 235.1

Step 2: Synthesis of2,2,2-trichloro-N-((5-chloro-2-cyanophenyl)(cyclohexyl)carbamoyl)-acetamide

A vial was charged under nitrogen with4-chloro-2-(cyclohexylamino)benzonitrile (1.0 equiv) and dry DCM (0.2M). The reaction vessel was cooled to 0° C. and 2,2,2-trichloroacetylisocyanate (1.0 equiv) was added. The reaction vessel was stirred for 1h at room temperature. The reaction mixture was cooled to 0° C. andwater 3 mL was added. The layers were extracted twice with DCM (2×5 mL).The combined organic fractions were dried, and the crude was usedwithout purification. m/z [M+H]⁺ 422.0

Step 3: Synthesis of 4-amino-7-chloro-1-cyclohexylquinazolin-2(1H)-one

A vial at −10° C. was charged under nitrogen with2,2,2-trichloro-N-((5-chloro-2-cyanophenyl)(cyclohexyl)carbamoyl)acetamide(1.0 equiv) followed by 7N NH₃ in methanol (20.0 equiv). The reactionvessel was stirred for 18 h at room temperature. The reaction mixturewas concentrated under vacuum and directly purified by reverse phasepurification (20-45% MeCN/water, 0.1% formic acid). ¹H NMR (400 MHz,DMSO-d₆) δ 7.74 (d, J=8.5 Hz, 1H), 7.58 (s, 1H), 7.19 (d, J=8.7 Hz, 1H),4.35 (s, 1H), 2.63-2.44 (m, 2H), 1.88 (d, J=13.7 Hz, 3H), 1.72 (d,J=12.6 Hz, 3H), 1.51 (dt, J=17.0, 11.5 Hz, 2H), 1.30 (q, J=13.3, 12.7Hz, 1H). m/z [M+H]⁺ 278.1 Example 9 Synthesis ofN-(3-(7-chloro-4-(dimethylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)-methanesulfonamide

A vial was charged with1-(3-bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (1equiv), tBuXPhosPd(allyl)OTf (johnson Matthey C4277, 0.1 equiv),methanesulfonamide (1.6 equiv), potassium carbonate (2.2 equiv) andacetonitrile (0.075 M). The vial was flushed with nitrogen, and thenheated to 80° C. for 18 h. The mixture was cooled to room temperature,diluted with DMSO, filtered and purified by reverse-phase prep HPLC(15-100% MeCN/water, 0.1% formic acid) to provide the title compound. ¹HNMR (400 MHz, DMSO-d₆) δ 8.04 (d, J=8.6 Hz, 1H), 7.56 (t, J=8.0 Hz, 1H),7.33 (d, J=8.3 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.07 (s, 1H), 7.03 (d,J=8.0 Hz, 1H), 6.41 (s, 1H), 3.30 (s, 6H), 3.06 (s, 3H). m/z [M+H]⁺393.0.

Example 10 Synthesis of7-chloro-4-(dimethylamino)-1-(3-(2-phenoxyethyl)phenyl)quinazolin-2(1H)-one

A vial was charged with1-(3-bromophenyl)-7-chloro-4-(dimethylamino)quinazolin-2(1H)-one (75 mg,0.178 mmol), AmPhos Pd(crotyl)Cl pre-catalyst (Johnson Mathey, Pd-161,0.1 equiv), potassium (2-phenyloxy)ethyltrifluoroborate (1.2 equiv),potassium carbonate (3 equiv) and toluene/water (5:1 0.1 M). The vialwas flushed with nitrogen and then heated to 100° C. for 1.3 hr. Themixture was cooled to room temperature, filtered and purified byreverse-phase prep HPLC (20-80% MeCN/water, 0.1% formic acid) to providethe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.03 (d, J=8.7 Hz, 1H),7.59-7.42 (m, 2H), 7.23 (p, J=8.6, 8.2 Hz, 4H), 7.14 (d, J=7.7 Hz, 1H),6.96-6.80 (m, 3H), 6.35 (s, 1H), 4.23 (t, J=6.6 Hz, 2H), 3.30 (s, 6H),3.11 (t, J=6.5 Hz, 2H). m z [M+H]⁺ 420.0

Example 11 Synthesis of2-(3-(7-Chloro-4-(methylamino)-2-oxoquinazolin-1(2H)-yl)phenyl)aceticAcid

To stirred solution of iodine (0.1 equiv) in acetonitrile (0.3 M) andwater (0.15 M) was added7-chloro-4-(methylamino)-1-(3-vinylphenyl)quinazolin-2(1H)-one (1equiv). After 5 min, Oxone® (2 equiv) was added portion wise and theresulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was diluted with water and extracted with EtOAc and thecombined organic layer was washed with water, brine and dried overanhydrous sodium sulfate. The dried organics were filtered andconcentrated under reduced pressure to obtain crude compound which waspurified by Prep-HPLC (MeCN/H₂O 60-100%, 0.1% Formic Acid) to afford thetitle compound as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.62(d, J=4.5 1H), 8.10 (d, J=8.5, 1H), 7.48 (t, J=8.0, 1H), 7.38 (d, J=7.5,1H), 7.25 (dd, J=11.0, 2.0 Hz, 1H), 7.15-7.11 (m, 2H), 6.33 (s, 1H),3.51 (s, 2H), 2.98 (d, J=4.5 3H). m/z [M+H]⁺ 344.30.

Example 12 Synthesis of5-methoxy-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one

A 20 mL vial under nitrogen was added5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-one(1.0 equiv), MeOH (0.6 M) and MeONa (5.4 N in MeOH, 10 equiv). Thereaction mixture was stirred for 60 minutes at 45° C. The reactionvessel was acidified by adding AcOH. The crude solution was purified byreverse phase chromatography (20-60% MeCN/water, with 0.1% Formic acid).¹H NMR (400 MHz, DMSO-d₆) δ 8.65 (bs, 1H), 7.60 (t, J=7.6 Hz, 2H), 7.53(d, J=6.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 2H), 7.07 (s, 1H), 6.13 (s, 1H),4.10 (s, 3H), 3.02 (d, J=3.9 Hz, 3H). m/z [M+H]⁺ 350.1.

Proceeding analogously as described above, following compound(s) wereprepared by substituting for5-fluoro-4-(methylamino)-1-phenyl-7-(trifluoromethyl)quinazolin-2(1H)-oneas needed:

5-methoxy-4-(methylamino)-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-onewas prepared by using4-chloro-5-fluoro-7-(trifluoromethyl)-1-(2-(trifluoromethyl)pyridin-3-yl)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 8.94 (d, J=4.9 Hz, 1H), 8.39 (s, 1H), 8.18(d, J=8.1 Hz, 1H), 8.02 (t, J=6.5 Hz, 1H), 7.81-7.57 (m, 4H), 6.41 (s,1H), 3.04 (s, 3H), 2.36 (d, J=2.1 Hz, 3H).

5-Methoxy-4-(methyl amino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one was prepared by using 5-chloro-4-(methylamino)-1-(o-tolyl)-7-(trifluoromethyl) quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.67-8.66 (m, 1H), 7.47-7.38 (m, 3H), 7.14(dd, J=1.5, 1.5 Hz, 1H), 7.08 (s, 1H), 6.02 (d, J=1 Hz, 1H), 4.1 (s,3H), 3.02 (d, J=4.5 Hz, 3H), 1.94 (s, 3H). m/z [M+H]⁺ 364.19.

7-Chloro-1-(2-chlorophenyl)-5-methoxy-4-(methylamino)quinazolin-2(1H)-onewas prepared by using7-chloro-1-(2-chlorophenyl)-5-fluoro-4-(methylamino)quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d6) δ 8.57 (d, J=4.5 Hz, 1H), 7.73-7.72 (m, 1H),7.57-7.54 (m, 2H), 7.47-7.46 (m, 1H), 6.95 (d, J=2.0 Hz, 1H), 5.78 (d,J=2.0 Hz, 1H), 4.04 (s, 3H), 3.00 (d, J=4.5 Hz, 3H). m/z [M+H]⁺ 350.2.

7-Chloro-5-methoxy4-((trans-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using7-Chloro-5-fluoro-4-((trans-3-methoxycyclobutyl)amino)-1-(o-tolyl)quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.36 (d, J=6.5 Hz, 1H), 7.45-7.36 (m, 3H),7.17 (d, J=7.0 Hz, 1H), 6.95 (d, J=2.0 Hz, 1H), 5.78 (d, J=2.0 Hz, H),4.70-4.63 (m, 1H), 4.07 (s, 3H), 4.04-4.02 (m, 1H), 3.19 (m, 3H),2.37-2.33 (m, 4H), 1.93 (s, 3H). m/z [M+H]⁺ 400.33.

7-Chloro-4-((2,2-difluoroethyl)amino)-5-methoxy-1-(o-tolyl)quinazolin-2(1H)-onewas prepared by using7-Chloro-4-((2,2-difluoroethyl)amino)-5-fluoro-1-(o-tolyl)quinazolin-2(1H)one.

¹H NMR (500 MHz, DMSO-d₆) δ 8.65 (t, J=5.5 Hz, 1H), 7.46-7.37 (m, 3H),7.19 (dd, J=7.5, 1.5 Hz, 1H), 6.97 (d, J=1.5 Hz, 1H), 6.43-6.18 (m, 1H),5.80 (d, J=1.5 Hz, 1H), 4.05 (s, 3H), 4.03-3.91 (m, 2H), 1.94 (s, 3H).m/z [M+H]⁺ 380.35.

Example 13 Synthesis of(S)-4-(pyrrolidin-3-ylamino)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-one

A 20 mL vial was added tert-butyl(S)-3-((2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)amino)pyrrolidine-1-carboxylate(1.0 equiv), MeCN (0.6 M) and HCl (4N in Doxane, 25 equiv). The reactionmixture was stirred for 30 minutes 45° C. The reaction vessel wasconcentrated using the genevac. The crude was purified by reverse phasechromatography (10-40% ACN/water, with 0.1% Formic acid). ¹H NMR (400MHz, MeCN-d₃) δ 8.87 (s, 1H), 8.58 (d, J=8.4 Hz, 1H), 8.38 (s, 1H), 7.60(d, J=8.4 Hz, 1H), 7.54-7.38 (m, 3H) 7.25 (d, J=7.6 Hz, 1H), 6.44 (s,1H), 4.85-4.72 (m, 1H), 3.80-2.94 (m, 4H), 2.24-2.11 (m, 1H), 2.03-1.88(m, 1H), 1.95 (s, 3H). m/z [M+H]⁺ 389.15.

Proceeding analogously as described above,(S)-4-(3-(methylamino)pyrrolidin-1-yl)-1-(o-tolyl)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by using tert-butyl(S)-methyl(1-(2-oxo-1-(o-tolyl)-7-(trifluoromethyl)-1,2-dihydroquinazolin-4-yl)pyrrolidin-3-yl)carbamate.

¹H NMR (400 MHz, Methanol-d₄) δ 8.35 (d, J=8.6 Hz, 1H), 7.49-7.31 (m,4H), 7.11 (d, J=7.6 Hz, 1H), 6.60 (s, 1H), 4.20-4.00 (m, 3H), 3.97-3.89(m, 1H), 3.64-3.56 (m, 1H), 2.54 (s, 3H), 2.40-2.26 (m, 1H), 2.16-2.02(m, 1H), 1.94 (s, 3H). m/z [M+H]⁺ 403.1

Example 14 Synthesis of1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)-6-(methylthio)quinazolin-2(1H)-one

To a solution of6-bromo-1-(2-chlorophenyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one(1 equiv.) in dimethyl sulfoxide (0.05 M) was added copper (I) iodide (2equiv.) and dimethyl amine in THF (2 M, 4 equiv.). The reaction mixturewas heated to 90° C. for 18 h and then cooled. The crude reactionmixture was filtered and purified via reverse phase columnchromatography (20-60% MeCN/water, 0.1% formic acid) to give the titlecompound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.69-8.62 (m, 1H), 7.85 (s, 1H),7.71 (d, J=4.3 Hz, 1H), 7.58-7.51 (m, 2H), 7.46-7.39 (m, 1H), 5.77 (s,1H), 3.02-2.97 (m, 3H), 2.55 (s, 3H), 1.99 (p, J=6.5 Hz, 1H), 0.91 (d,J=8.1 Hz, 2H), 0.24 (d, J=4.9 Hz, 2H). m/z [M+H]⁺ 372.0.

Proceeding analogously as described above,1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-onewas prepared by using1-(2-chlorophenyl)-7-cyclopropyl-4-((cyclopropylmethyl)amino)-6-(methylthio)quinazolin-2(1H)-one.

¹H NMR (400 MHz, DMSO-d₆) δ 8.80-8.73 (m, 1H), 7.96 (s, 1H), 7.75-7.69(m, 1H), 7.59-7.51 (m, 2H), 7.47-7.41 (m, 1H), 5.76 (s, 1H), 3.43 (dt,J=12.0, 5.8 Hz, 2H), 2.57 (s, 3H), 2.08-2.00 (m, 1H), 1.23 (dt, J=13.0,7.1 Hz, 1H), 0.92 (d, J=7.8 Hz, 2H), 0.50 (d, J=7.4 Hz, 2H), 0.35-0.29(m, 2H), 0.23 (d, J=4.6 Hz, 2H). m/z [M+H]⁺ 412.0.

Example 15

1-((1H-imidazol-4-yl)methyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-one

A vial was charged with4-(methylamino)-7-(trifluoromethyl)-1-((1-((2-(trimethylsilyl)-ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one(1.0 equiv) and DCM (0.5 M). TFA (6 equiv) was added at 0° C. and thereaction mixture was stirred allowing to warm to room temperature for 16h. Purification by preparative HPLC afforded the title product as amixture of enaniomers. SFC purification (30% MeOH, Lux Cellulose-2,peak 1) ¹H NMR (500 MHz, DMSO-d₆) δ 11.96 (s, 1H), 8.59 (d, J=4 Hz, 1H),8.21 (d, J=8.5 Hz, 1H), 7.98 (s, 1H), 7.54-7.46 (m, 2H), 6.94 (s, 1H),5.20 (s, 2H), 2.97-2.94 (m, 3H). m/z [M+H]⁺ 324.35.

Proceeding analogously as described above, the following compounds wereprepared:

(R)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting for4-(methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazolin-2(1H)-one.SFC purification (30% MeOH, Lux Cellulose-2, peak 1).

¹H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (m, 1H), 8.17 (d, J=8.5 Hz, 1H),7.66 (s, 1H), 7.55 (s, 1H), 7.45-7.40 (m, 1H), 7.07 (s, 1H), 6.50 (q,J=7 Hz, 1H), 2.95 (d, J=8.5 Hz, 3H), 1.72 (d, J=7.0 Hz, 3H). m/z [M+H]338.3.

(S)-1-(1-(1H-imidazol-4-yl)ethyl)-4-(methylamino)-7-(trifluoromethyl)quinazolin-2(1H)-onewas prepared by substituting for4-(methylamino)-7-(trifluoromethyl)-1-(1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)ethyl)quinazolin-2(1H)-one.SFC purification (30% MeOH, Lux Cellulose-2, peak 2).

¹H NMR (500 MHz, DMSO-d6) δ 8.58-8.57 (m, 1H), 8.17 (d, J=8.5 Hz, 1H),7.66 (s, 1H), 7.55 (s, 1H), 7.45-7.40 (m, 1H), 7.07 (s, 1H), 6.50 (q,J=7 Hz, 1H), 2.95 (d, J=8.5 Hz, 3H), 1.72 (d, J=7.0 Hz, 3H). m/z [M+H]338.3.

1-((1H-imidazol-4-yl)methyl)-7-cyclopropyl-4-(methylamino)quinazolin-2(1H)-one was prepared by substituting with7-cyclopropyl-4-(methylamino)-1-((1-((2-(trimethylsilyl)ethoxy)methyl)-1H-imidazol-4-yl)methyl)quinazolin-2(1H)-one.

¹H NMR (500 MHz, DMSO-d6) δ 8.18-8.20 (m, 1H), 7.84 (d, J=8.5 Hz, 1H),7.53 (s, 1H), 7.25 (d, J=1 Hz, 1H), 6.85-6.81 (m, 2H), 5.14 (s, 1H),2.91 (d, J=4.5 Hz, 3H), 1.94-1.92 (m, 1H), 1.04-1.00 (m, 2H), 0.98-0.97(m, 2H). m/z [M+H]⁺ 294.4.

BIOLOGICAL EXAMPLES Example 1 Biochemical Assays

The ability of the compound of present disclosure to inhibit MAT2Aenzyme was determined using the Malachite Green or Phosphate SensorFluorescence Assay described below.

A. Malachite Green Assay Materials:

Enzyme: MAT2A

-   -   hMAT2A: 50 nM, Cepter, 10 mg/mL (234 μM), amino acids 1-395    -   Substrates: 500 uM each    -   Reaction time: 1 hour

L-methionine Substrate: Alfa Aesar catalog #J61904

ATP Substrate: Alfa Aesar cat #J60336

Malachite Green Detection Reagent: Millipore Sigma catalog #MAK307-1KT

Assay buffer: 50 mM Tris, pH 7.5/50 mM KCl/10 mM MgCl₂/0.01% Brij-35/1mM DTT/0.1% BGG

Temperature: 23° C.

Total volume: 20 μL

Controls:

0% inhibition control: DMSO

100% inhibition control: No enzyme

Procedure:

5 μL of 3×final concentration test compounds in DMSO or DMSO weretransferred to the appropriate wells of a microtiter plate and the platewas centrifuged at 1000 rpm for 1 minute. 5 μL of 3×final concentrationMAT2A enzyme in assay buffer or assay buffer alone was transferred tothe appropriate wells and the plate was centrifuged at 1000 rpm for 1minute. The plate was incubated at room temperature for 15 minutes andthen 5 μL of 3× the L-methionine and ATP substrate mixture in assaybuffer was transferred to all the test wells. The plate was centrifugedat 1000 rpm for 1 minute and then incubated at room temperature for 1hour. 5 μL of malachite green detection reagent was added to all thetest wells and the plate was centrifuged at 1000 rpm for 1 minute andthen incubated at room temperature for 30 minutes. The plate was readfor absorbance at 620 nm on a plate reader (e.g., Infinite M1000). Thehigh control (DMSO) with high absorbance represents no inhibition ofenzymatic reaction while the low control (no enzyme) with low absorbancerepresents full inhibition of enzymatic reaction.

The IC₅₀ of a representative number of compounds in Table 1 above aredisclosed in Table 3 below:

(+) IC₅₀=10 uM-1 uM; (++) IC₅₀=1 uM-500 nM; (+++) IC₅₀'₂ 500 nM-200 nM;(++++) IC₅₀<200 nM; (+++++)<10 nm

TABLE 3 Cpd. No. Cpd. No. Cpd. No. (Table 1) IC₅₀ um (Table 1) IC₅₀ um(Table 1) IC₅₀ um 2 ++++ 36 ++++ 70 ++++ 3 ++++ 37 ++++ 73 ++++ 4 +++ 38++++ 74 ++++ 5 ++++ 39 ++++ 75 ++++ 6 ++++ 42 +++ 76 ++++ 7 ++++ 43 + 77++++ 8 + 44 ++++ 80 ++++ 10 +++ 45 ++++ 81 ++++ 11 ++++ 46 ++++ 82 ++++12 +++ 47 ++++ 14 ++++ 48 ++++ 15 ++++ 49 ++++ 17 ++++ 50 ++++ 18 ++++51 ++++ 21 +++ 52 ++++ 22 +++ 54 ++++ 23 +++ 55 ++++ 24 ++++ 56 ++++ 25++++ 57 ++++ 26 ++++ 59 ++++ 27 + 60 ++++ 28 +++ 61 ++++ 29 + 62 +++ 31++ 63 + 32 +++ 64 + 34 ++++ 66 ++++ 35 ++++ 67 ++++

B. Phosphate Sensor Fluorescence Assay

MAT2A enzyme is incubated with a test compound in DMSO or DMSO and itssubstrates (L-methionine and ATP) in a microtiter plate. The enzymaticreaction is stopped by the addition of Working Phosphate Sensor Mixture.The plate is analyzed for fluorescence at 450 nm. The high control (DMSOwith enzyme and its substrates) gives high fluorescence which representsno inhibition of enzymatic activity while the low control (DMSO withMAT2A substrates and no enzyme) gives low fluorescence which representsfull inhibition of enzymatic activity.

Materials:

Human MAT2A: Cepter, amino acids 1-395

Tris, pH 7.5: Invitrogen cat #15567-027

KCl: Ambion cat #AM9640G

MgCl₂: Ambion cat #AM9530G

Brij-35: Sigma cat B4184-10ML

DTT: Goldbio cat #DTT100

BGG: Sigma cat #G5009-25G

PNP: Novus Biologicals cat #NBP1-50872

7-MEG: Cayman Chemical cat #15988

L-Methionine: Alfa Aesar cat #J61904

ATP: Alfa Aesar cat #J60336

Phosphate Sensor: Thermo Fisher cat #PV4407

EDTA: Life Tech cat #15575-038

Assay plate: 384-well black polypropylene plate: Thomas Scientific cat#1149Q35

Final Assay Conditions:

Assay Buffer: 50 mM Tris, pH 7.5/50 mM KCl/10 mM MgCl₂/0.01% Brij-35/1mM DTT/0.1% BGG/40 nM PNP/6 uM 7-MEG

MAT2A: 10 nM for Cepter clone ID 329, lot 00023-123 before the additionof Working Phosphate Sensor Mixture

-   -   5 nM for Cepter clone ID 334, lot 00023-148 before the addition        of Working Phosphate Sensor Mixture

L-methionine: 500 uM before the addition of Working Phosphate SensorMixture

ATP: 500 uM before the addition of Working Phosphate Sensor Mixture

Procedure:

For the assay, a mixture of 1 mM L-methionine/1 mM ATP (2× finalpre-stopped concentration) in assay buffer; MAT2A (2× final pre-stoppedconcentration) in Assay Buffer and Working Phosphate Sensor Mixture (1.5uM Phosphate Sensor/30 mM EDTA in Assay Buffer, which is 3× finalconcentrations) were prepared. Test compounds or DMSO were added to theappropriate well suing D300e digital dispenser. 5 μl/well of AssayBuffer was added to the wells corresponding to the negative control and5 μl/well of MAT2A was added to all the wells except for thosecorresponding to the negative control. After incubating the plate atroom temperature for 15 minutes, 5 μl/well of the 1 mM L-methionine/1 mMATP mixture was added to all wells. The plate was centrifuged at 1000rpm for 1 minute and then incubated at room temperature for 1 hour. 5 μlof the Working Phosphate Sensor Mixture was added to all wells and theplate was centrifuged at 1000 rpm for 1 minute. The plate was read forfluorescence at 450 nm after exciting at 430 nm.

Data Analysis:

Percent inhibition was calculated in Chemical and Biological InformationSystem (CBIS), (ChemInnovation Software Inc.). Curves were fitted byCBIS as % inhibition vs. log [compound concentration] using a4-parameter inhibition model.

Fit=(A+((B−A)/(1+((C/x){circumflex over ( )}D))))

Res=(y−fit)

The IC₅₀ of a representative number of compounds in Table 1 above aredisclosed in Table 4 below:

(+) IC₀=10 uM-1 uM; (++) IC₀=1 uM-500 nM; (+++) IC₅₀=500 nM-200 nM;(++++) IC₀<200 nM

TABLE 4 Cpd No (Table 1) IC₅₀ um  85 >10  86 +++  87 ++++  88 ++++  80++++  90 +++  91 ++++  92 +++  93 >10  94 ++  94 +  96 ++++  97 ++++  98++++  99 ++++ 100 ++++ 101 ++++ 102 ++++ 103 ++++ 104 >10 105 +++ 106 +107 ++++ 108 >10 109 ++++ 110 ++++ 112 >10 113 >10 114 ++++ 115 ++++116 >10 117 + 118 ++++ 119 ++++ 120 + 121 +++ 122 ++++ 123 +++ 124 ++125 ++++ 126 ++++ 127 ++++ 128 ++++ 129 ++++ 130 ++ 132 >10 133 ++++ 134++++ 135 ++++ 136 ++++ 137 ++++ 138 ++++ 139 ++++ 140 ++++ 141 ++++ 142++++ 143 ++++ 144 +++ 145 ++++ 146 ++++ 147 ++++ 148 ++++ 149 ++++ 150++++ 151 ++++ 152 ++++ 153 ++++ 154 ++++ 155 +++ 156 + 157 ++++ 159 ++++160 ++++ 161 ++++ 162 ++++ 163 ++++ 164 ++++ 165 ++++ 166 +++ 167 ++++168 ++++ 169 ++++ 170 ++++ 171 ++++ 172 ++++ 173 ++++ 174 >10 175 ++++176 ++++ 177 ++++ 178 ++++ 179 ++++ 180 ++++ 181 ++++ 182 ++++ 183 ++++184 ++++ 185 ++++ 186 ++++ 187 +++ 188 +++ 189 ++++ 190 + 191 >10192 >10 193 >10 194 >10 195 >10 196 ++++ 197 ++++ 188 ++ 199 ++++ 200 +201 ++++ 202 >10 203 +++ 204 ++++ 205 ++++ 206 >10 207 ++++ 208 >10209 >10 210 >10 211 ++ 212 >10 213 + 214 ++++ 215 >10 216 ++++ 217 +++218 ++++ 219 +++ 220 + 221 + 222 ++++ 223 ++++ 224 >10 225 ++++ 226 ++++227 ++++ 228 >10 229 >10 230 ++++ 231 + 232 ++++ 233 ++++ 234 ++++ 235++++ 236 >10 237 ++++ 238 ++++ 239 ++++ 240 + 241 + 242 ++ 243 >10 244++++ 245 ++++ 246 ++++ 247 ++++ 248 ++++ 249 >10 250 ++ 251 + 252 >10253 >10 254 ++++ 255 ++++ 256 ++++ 257 ++++ 258 ++++ 259 ++++ 260 ++++261 ++++ 262 ++++ 263 ++++ 264 ++++ 265 ++++ 266 + 267 + 268 ++++ 269++++ 270 ++++ 271 ++++ 272 ++++ one of 273 + and 292 is and the other of273 and 292 is ++++ 274 ++++ 275 ++ 276 + 277 ++++ 278 ++++ 279 ++++ 280++++ 281 ++++ 282 ++++ 283 ++++ 284 ++++ 285 ++++ 286 ++++ 287 ++++288 >10 289 >10 290 >10 291 >10 400 ++++ 293 ++++ 294 ++++ 295 ++++ 296++++ 297 ++++ 288 ++++ 299 +++ 300 ++++ 301 ++++ 302 ++++ 303 ++++ 304++++ 305 >10 306 ++++ 307 ++++ 308 ++++ 309 + 310 ++++ 311 >10 312 ++++313 ++ 314 ++++ 315 ++++ 316 +++ 317 ++++ 318 ++++ 319 ++++ 320 ++++ 321++++ 322 ++++ 323 ++++ 324 ++++ 325 ++++ 326 ++++ 327 ++++ 328 ++++ 329++++ 330 >10 331 ++++ 332 >10 333 ++++ 334 ++++ 335 ++++ 336 ++++ 337++++ 338 ++++ 339 ++++ 340 +++ 341 ++++ 342 >10 343 >10 344 ++++ 345++++ 346 ++++ 347 ++++ 348 ++++ 349 >10 350 ++++ 351 ++++ 352 ++++ 353++++ 354 >10 355 ++++ 356 >10 357 + 358 ++++ 359 ++++ 360 >10 361 >10362 ++++ 363 ++++ 364 ++++ 365 ++++ 366 ++++ 367 ++++ 368 ++++ 369 ++++370 ++++ 371 ++++ 372 ++++ 373 ++++ 374 ++++ 375 >10 376 ++++ 377 ++++378 ++++ 379 ++++ 380 ++++ 381 ++++ 382 >10 383 ++ 384 ++++ 385 ++++ 386++++ 387 + 388 ++++ 389 ++++ 390 ++++ 391 ++++ 392 >10 393 >10 394 ++++395 ++++ 396 +++ 397 ++++ 398 ++++ 399 ++++ 401 +++ 402 ++ 403 + 404++++ 405 ++++ 406 +++ 407 ++++ 408 ++ 409 ++++ 410 ++++ 411 ++++ 412++++ 413 ++++ 414 ++++ 415 ++++ 416 ++++ 417 ++++ 418 ++++ 419 ++++ 420++++ 421 ++++ 422 ++++ 423 ++++ 424 ++++ 425 ++++ 426 ++++ 427 to 776++++

What is claimed:
 1. A compound of Formula (IA′):.

where: w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N,wherein: R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano,amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy,heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocyclylalkyloxy, heterocyclyloxyalkoxy, orheterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itselfor as part of another group, is unsubstituted or substituted with R^(a),R^(b), and/or R^(c) independently selected from alkyl, cycloalkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R⁵ is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy,cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl,heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino,wherein heterocyclyl or heteroaryl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(a), R^(b), and/or R^(c)independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy,alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,cyano, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) no morethan two of w, x, y, and z can be N and (ii) at least one of R³, R⁴, R⁵,and R⁶ is other than hydrogen; R¹ is R⁷ wherein R⁷ is cycloalkyl,bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl,heterocyclyl, bridged heterocyclyl, fused heterocyclyl, orspiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl isunsubstituted or substituted with R^(d), R^(e), and/or R^(f); R² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or —X^(b)—R¹¹wherein: R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fusedheterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridgedheterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, whereinaryl, heteroaryl, or heterocyclyl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(g), R^(h), and/or R^(i);R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R¹⁰ is hydrogen,alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl,alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl,substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fusedheterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl,spiroheterocyclyl, or spiroheterocyclylalkyl, wherein aryl, heteroaryl,or heterocyclyl, by itself or as part of another group, is unsubstitutedor substituted with R^(j), R^(k), and/or R^(l); X^(b) is a bond oralkylene; and R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fusedheterocyclyl, or spiroheterocyclyl, wherein heteroaryl or heterocyclylis unsubstituted or substituted with R^(m), R^(n), and/or R^(o); andR^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and R^(f), R^(i), R^(l), and R^(o) are independently selectedfrom alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo,amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹²where X^(c) is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; provided that when R¹ is heterocyclyl thenR^(f) is not hydroxy; or a pharmaceutically acceptable salt thereof;provided that: (1) when

where: (a) when R² is piperazin-1-yl, 2-methylpiperazin-1-yl, or1H-benzo[d][1,2,3]triazol-1-yl, R³ and R⁶ are hydrogen, R⁴ is chloro andR⁵ is bromo or 5-methylindazol-4-yl, then R¹ is not 2-isopropylphenyl;(b) when R² and R⁶ are methyl and R³, R⁴, and R⁵ are hydrogen; or R² andR³ are methyl and R⁴, R⁵, and R⁶ are hydrogen, then R¹ is not 2,5-, 2,6-or 2,8-dimethylquinolin-4-yl or 2-methyl-5-methoxy-, 2-methyl-6-methoxy-or 2-methyl-8-methoxyquinolin-4-yl; (c) when R² is amino or acetylamino,R⁴ is dimethylamino, and R³, R⁵, and R⁶ are hydrogen, then R is not4-hydroxy-5-hydroxymethyl-tetrahydrofuran-2-yl; (d) when R⁵ is fluoro,R³, R⁴ and R⁶ are hydrogen, and R² is4-aminocarbonylmethyl-2-methylphenylamino, then R¹ is not4-fluoro-2-(2-thiazol-2-ylmethoxy)phenyl,4-fluoro-2-(2-pyridin-2-ylmethoxy)phenyl, or 4-chloro-2-methoxyphenyl;(e) when R⁶ is fluoro, R³, R⁴ and R⁵ are hydrogen, and R² is4-aminocarbonylmethyl-2-methylphenylamino, then R¹ is not4-fluoro-2-methoxyphenyl; (f) when R¹ is 4-chloro-2-ethoxyphenyl, R⁵ isfluoro, and R³, R⁴ and R⁶ are hydrogen, then R² is not3-(2-oxoimidazolidin-1-yl)-2-methylphenylamino; (2) when

then when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, R⁵ is amino, and R³is methoxy; then R² is not amino; and (3) when

then when R¹ is 4-hydroxy-5-hydroxymethylfuran-1-yl, one of R⁴ and R⁵ ishydrogen, and the other of R⁴ and R⁵ is methyl or both of R⁴ and R⁵ aremethyl, then R² is not amino.
 2. The compound of claim 1 or apharmaceutically acceptable salt thereof having a structure of Formula(IA):

where: R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl,alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano,amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl, ordialkylaminocarbonyl; provided that: (i) no more than two of w, x, y,and z can be N and (ii) at least one of R³, R⁴, R⁵, and R⁶ is other thanhydrogen; R¹⁰ is hydrogen, alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl,alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl,substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fusedheterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl,spiroheterocyclyl, or spiroheterocyclylalkyl, wherein aryl, heteroaryl,or heterocyclyl, by itself or as part of another group, is unsubstitutedor substituted with R^(j), R^(k), and/or R^(l); and R^(f), R^(i), R^(l),and R^(o) are independently selected from alkyl, cycloalkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, amino, cycloalkylsulfonylamino,cyano, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl,aminocarbonylalkyl, or —X^(c)—R¹² where X^(c) is bond, alkylene, orheteroalkylene and R¹² is optionally substituted aryl, optionallysubstituted heteroaryl, and optionally substituted heterocyclyl;provided that when R¹ is heterocyclyl then R^(f) is not hydroxy;
 3. Thecompound of claim 2 or a pharmaceutically acceptable salt thereofwherein the compound has a structure of Formula (I):

where: R³ and R⁵ are independently hydrogen, alkyl, alkenyl, alkynyl,alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano,amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroarylamino,heterocyclyl, heterocyclyloxy, heterocyclylamino, heterocyclyloxyalkoxy,or heterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, byitself or as part of another group, is unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R¹ is R⁷ wherein R⁷ iscycloalkyl, bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl,phenyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fusedheterocyclyl, or spiroheterocyclyl, wherein phenyl, heteroaryl, orheterocyclyl is unsubstituted or substituted with R^(d), R^(e), and/orR^(f); R⁹ is hydrogen, alkyl or cycloalkyl; and R¹⁰ is hydrogen, alkyl,haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl,bridged cycloalkyl, bridged cycloalkylalkyl, fused cycloalkyl,spirocycloalkyl, spirocycloalkylalkyl, aryl, aralkyl, heteroaryl,heteroaralkyl, heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fusedheterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl,spiroheterocyclyl, or spiroheterocyclylalkyl, wherein aryl, heteroaryl,or heterocyclyl, by itself or as part of another group, is unsubstitutedor substituted with R^(j), R^(k), and/or R^(l); R^(d), R^(e), R^(g),R^(h), R^(j), R^(k), R^(m), and R^(n) are independently selected fromalkyl, haloalkyl, haloalkoxy, alkoxy, alkylsulfonyl, halo, cyano,carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,heterocyclylcarbonyl, and ureido; and R^(f), R^(i), R^(l), and R^(o) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, halo, cyano, or —X^(c)—R¹² where X^(c) is bond, alkylene orheteroalkylene and R¹² is optionally substituted aryl, optionallysubstituted heteroaryl, or optionally substituted heterocyclyl
 4. Thecompound of any one of claims 1 to 3, or a pharmaceutically acceptablesalt thereof having a structure of formula (IIIa), (IIIb), (IIIc),(IIId), (IIIe), or (IIIg) below:


5. The compound of claim 4, or a pharmaceutically acceptable saltthereof having structure of formula (IIIa).
 6. The compound of claim 4,or a pharmaceutically acceptable salt thereof having structure offormula (IIId).
 7. The compound of any one of claims 1 to 6 or apharmaceutically. acceptable salt thereof wherein R² is —NR⁹R¹⁰.
 8. Thecompound of any one of claims 1 to 6 or a pharmaceutically. acceptablesalt thereof wherein R² is —OR⁸.
 9. The compound of any one of claims 1to 6 or a pharmaceutically. acceptable salt thereof wherein R² is R¹¹.10. The compound of any one of claims 1 to 7 or a pharmaceutically.acceptable salt thereof wherein R⁹ is deuteroalkyl.
 11. The compound ofany one of claims 1 to 7 or a pharmaceutically acceptable salt thereofwherein R⁹ is hydrogen.
 12. The compound of any one of claims 1 to 7 ora pharmaceutically acceptable salt thereof wherein R⁹ is alkyl.
 13. Thecompound of claim 12 or a pharmaceutically acceptable salt thereofwherein R⁹ is methyl or ethyl.
 14. The compound of any one of claims 1to 7 and 12 to 13 or a pharmaceutically acceptable salt thereof whereinR¹⁰ is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,aminoalkyl, alkylcarbonyl, alkoxycarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, alkylaminocarbonylalkyl, ordialkylaminocarbonylalkyl.
 15. The compound of claim 14 or apharmaceutically acceptable salt thereof wherein R¹⁰ is hydrogen. 16.The compound of claim 8 or 14 or a pharmaceutically acceptable saltthereof wherein R⁸ and R¹⁰ are alkyl.
 17. The compound of claim 16 or apharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ are methyl.18. The compound of 1 to 8 and 12 to 13 or a pharmaceutically acceptablesalt thereof wherein R⁸ and R¹⁰ are independently cycloalkyl orcycloalkylalkyl, each ring may independently be unsubstituted orsubstituted with one or two substituents independently selected fromalkyl, halo, or cyano.
 19. The compound of claim 18 wherein R⁸ and R¹⁰are independently cyclopropyl, cyclobutyl, 1-methylcyclopropyl,(cis)-3-hydroxy-3-methylcyclobutyl,(cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl,cyclopropylmethyl, 1-hydroxycyclopropmethyl, 1-fluorocyclopropmethyl,(trans)-3-hydroxy-1-methylcyclobutyl, (cis)-3-cyanocyclobutyl,1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl,(trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl,(2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl,(1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl,(1R,2R)-2-fluorocyclopropyl, 1-fluorocyclopropylmethyl,(1S,2R)-2-fluorocyclopropyl, (1R,2S)-2-fluorocyclopropyl,(1S,2S)-2-fluorocyclopropyl, 2,2-difluorocyclopropyl,(R)-1-cyclopropylethyl, or 2,2-difluorocyclopropylmethyl.
 20. Thecompound of claim 18 wherein R⁸ and R¹⁰ are independently cyclopropyl,cyclobutyl, 1-methylcyclopropyl, (cis)-3-hydroxy-3-methylcyclobutyl,(cis)-3-hydroxy-2,2-dimethylcyclobutyl, 1-cyanocyclobutyl,(trans)-3-hydroxy-1-methylcyclobutyl (cis)-3-cyanocyclobutyl,1-methylcyclobutyl, (cis)-3-hydroxycyclobutyl,(trans)-3-hydroxycyclobutyl, (trans)-3-cyanocyclobutyl,(2S,1R)-2-hydroxycyclobutyl, (1S,2S)-2-hydroxycyclobutyl,(1S,2R)-2-hydroxycyclobutyl, (1R,2R)-2-hydroxycyclobutyl,(1R,2R)-2-fluorocyclopropyl, (1S,2R)-2-fluorocyclopropyl,(1R,2S)-2-fluorocyclopropyl, (1S,2S)-2-fluorocyclopropyl, or2,2-difluorocyclopropyl.
 21. The compound of claim 18 wherein R⁸ and R¹⁰are independently cyclopropylmethyl, 1-hydroxycyclopropmethyl,1-fluorocyclopropmethyl, 1-fluorocyclopropylmethyl,(R)-1-cyclopropylethyl, or 2,2-difluorocyclopropylmethyl.
 22. Thecompound of 1 to 8 and 12 to 13 or a pharmaceutically acceptable saltthereof wherein R⁸ and R¹⁰ are independently heteroaryl or heteroaralkylwherein heteroaryl, by itself or as part heteroaralkyl, is unsubstitutedor substituted with R^(j), R^(k), and/or R^(l).
 23. The compound ofclaim 22 wherein R⁸ and R¹⁰ are heteroaryl independently selected frompyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thienyl, pyrrolyl,pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolinyl,isoquinolinyl, indolyl, and indazolyl, each ring is either unsubstitutedor substituted with R^(j), R^(k), and/or R^(l).
 24. The compound ofclaim 22 or a pharmaceutically acceptable salt thereof wherein R⁸ andR¹⁰ are heteroaryl independently selected from pyrazolyl, imidazolyl,thienyl, pyrrolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl,quinolinyl, isoquinolinyl, indolyl, and indazolyl, each ring is eitherunsubstituted or substituted with R^(j), R^(k), and/or R^(l).
 25. Thecompound of claim 22 or a pharmaceutically acceptable salt thereofwherein R⁸ and R¹⁰ are heteroaralkyl independently selected frompyrazolylmethyl, pyrazolylethyl, oxazolylmethyl, isoxazolylmethyl,imidazolylmethyl, imidazolylethyl, thienylmethyl, thienylethyl,pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl, pyridinylethyl,pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl, pyrazinylethyl,pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl, quinolinylethyl,isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl, indolylethyl,indazolylmethyl and indazolylethyl, each ring is either unsubstituted orsubstituted with R^(j), R^(k), and/or R^(l).
 26. The compound of claim22 or a pharmaceutically acceptable salt thereof wherein R⁸ and R¹⁰ areheteroaralkyl independently selected from pyrazolylmethyl,pyrazolylethyl, imidazolylmethyl, imidazolylethyl, thienylmethyl,thienylethyl, pyrrolylmethyl, pyrrolylethyl, pyridinylmethyl,pyridinylethyl, pyrimidinylmethyl, pyrimidinylethyl, pyrazinylmethyl,pyrazinylethyl, pyridazinylmethyl, pyridazinylethyl, quinolinylmethyl,quinolinylethyl, isoquinolinylmethyl, isoquinolinylethyl, indolylmethyl,indolylethyl, indazolylmethyl and indazolylethyl, each ring is eitherunsubstituted or substituted with R^(j), R^(k), and/or R^(l).
 27. Thecompound of claim 22 or a pharmaceutically acceptable salt thereofwherein R⁸ and R¹⁰ are 1-methyl-1H-pyrazol-5-yl, isoxazol-4-yl,3-methyl-1,2,4-oxadiazol-5-yl, 5-methylisoxazol-3-yl,5-methylisoxazol-4-yl, 3-methoxyisoxazol-5-yl,3,5-dimethylisoxazol-4-yl, 3-methylisoxazol-4-yl, thiazol-4-yl,thiazol-5-yl, isothiazol-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl,2-(difluoromethyl)pyridin-4-yl, 2-(difluoromethoxy)pyridin-4-yl,5-methoxypyridin-3-yl, 6-methylpyridin-3-yl, 6-methoxypyridin-3-yl,3-cyanopyridin-4-yl, 3-methoxypyridin-4-yl, 3-fluoropyridin-4-yl,3-chloropyridin-4-yl, 2-(trifluoromethyl)pyridin-4-yl,2-methylpyridin-4-yl, pyrimidin-5-yl, 1-methyl-1H-imidazol-4-yl,1-methylpyrazol-3-ylmethyl, 3-methoxyisoxazol-5-ylmethyl,oxazol-2-ylmethyl, oxazol-4-ylmethyl, oxazol-5-ylmethyl,isoxazol-3-ylmethyl, isoxazol-4-ylmethyl, isoxazol-5-ylmethyl,1-methyl-1H-pyrazol-3-ylmethyl, 1-methyl-1H-pyrazol-4-ylmethyl,1-methyl-1H-pyrazol-5-ylmethyl, pyridin-4-ylmethyl, pyridin-3-ylmethyl,or pyridin-2-ylmethyl.
 28. The compound of any one of claims 1 to 6 or apharmaceutically acceptable salt thereof wherein R² is R¹¹ wherein R¹¹is heterocyclyl which is unsubstituted or substituted with R^(m), R^(n),and/or R^(o).
 29. The compound of claim 29 or a pharmaceuticallyacceptable salt thereof wherein R¹¹ is oxetanyl, azetidinyl,2-oxoazetidinyl, pyrrolidinyl, 2-oxopyrrolidinyl, piperidinyl,piperazinyl, or morpholinyl, each ring is unsubstituted or substitutedwith R^(m), R^(n), and/or R^(o).
 30. The compound of claim 28 or apharmaceutically acceptable salt thereof wherein R¹¹ is azetidin-1-yl,4-hydroxyazetidin-1-yl, 4-methylaminocarbonylazetidin-1-yl,4-dimethylaminocarbonylazetidin-1-yl, 2-hydromethyl-azetidin-1-yl,2-methylazetidin-1-yl, 2-oxoazetidin-1-yl, pyrrolidin-1-yl,2-oxopyrrolidin-1-yl, 3-hydroxypyrrolidin-1-yl,3,3-dimethylpyrrolidin-1-yl, 3-methoxypyrrolidin-1-yl,3-hydroxy-3-methylpyrrolidin-1-yl, piperidin-1-yl,2-carboxypiperidin-1-yl, 2-aminocarbonylpiperidin-1-yl, piperazin-1-yl,4-methylpiperazin-1-yl, or morpholin-4-yl.
 31. The compound of any oneof claims 1 to 30, or a pharmaceutically acceptable salt thereof whereinR⁵ is alkyl, alkoxy, halo, haloalkyl, haloalkoxy, cycloalkyl, cyano,aminocarbonyl, heteroaryl, heterocyclyl, wherein heterocyclyl orheteroaryl is unsubstituted or substituted with R^(a), R^(b), and/orR^(c) independently selected from alkyl, cycloalkyl, haloalkyl,haloalkoxy, alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, oraminoalkyl.
 32. The compound of claim 31, or a pharmaceuticallyacceptable salt thereof wherein R⁵ is methyl, ethyl, isopropyl,tert-butyl, methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl,difluoromethyl, trifluoromethoxy, difluoromethoxy, cyclopropyl,cyclopentyl, cyano, pyrazolyl, imidazolyl, thienyl, thiazolyl, oxazolyl,isoxazolyl, pyridinyl, pyrimidinyl, oxetan-3-yl, pyrrolidin-1-yl,tetrahydrofuranyl, 2-oxoazetidin-1-yl, or 2-oxopyrrolidin-1-yl, whereinheterocyclyl or heteroaryl rings are unsubstituted or substituted withR^(a), R^(b), and/or R^(c) independently selected from alkyl,cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano,hydroxyalkyl, alkoxyalkyl, or aminoalkyl.
 33. The compound of claim 31,or a pharmaceutically acceptable salt thereof wherein R⁵ is chloro,methyl, ethyl, trifluoromethyl, 1,1-difluoroethyl, or cyclopropyl. 34.The compound of claim 32 wherein R⁵ is chloro, trifluoromethyl, orethyl.
 35. The compound of any one of claims 1 to 34, or apharmaceutically acceptable salt thereof wherein R⁴ and R⁶ areindependently selected from hydrogen, methyl, chloro, fluoro, bromo,methoxy, methylthio, methylsulfonyl, trifluoromethyl, trifluoromethoxy,cyano, amino, methylamino, dimethylamino, methylaminocarbonyl, ordimethylaminocarbonyl.
 36. The compound of claim 35, or apharmaceutically acceptable salt thereof wherein R⁴ is hydrogen, fluoro,bromo, methyl, methoxy, or cyano and R⁶ is hydrogen.
 37. The compound ofany one of claims 1 to 34, or a pharmaceutically acceptable salt thereofwherein R⁴ and R⁶ are hydrogen.
 38. The compound of any one of claims 1to 37, or a pharmaceutically acceptable salt thereof wherein R³ ishydrogen, alkyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy,cycloalkyl, cyano, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl.
 39. The compound of 38 or apharmaceutically acceptable salt thereof wherein R³ is hydrogen ormethoxy.
 40. The compound of 38 or a pharmaceutically acceptable saltthereof wherein R³ is hydrogen
 41. The compound of 38 or apharmaceutically acceptable salt thereof wherein R³ is methyl, ethyl,methoxy, ethoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl,trifluoromethoxy, difluoromethoxy, cyclopropyl, cyano, methylsulfonyl,aminocarbonyl, methylamino, or dimethylamino.
 42. The compound of anyone of claims 1 to 41, or a pharmaceutically acceptable salt thereofwherein R¹ is R⁷ wherein R⁷ is phenyl which is unsubstituted orsubstituted with R^(d), R^(e), and/or R^(f) where R^(d) and R^(e) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R^(f) isselected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, andcyano,
 43. The compound of any one of claims 1 to 41, or apharmaceutically acceptable salt thereof wherein R^(t) is R⁷ wherein R⁷is phenyl which is unsubstituted or substituted with R^(d), R^(e),and/or R^(f) where R^(d) and R^(e) are independently selected frommethyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy, cyclopropyl,cyano, methylsulfonyl, methoxymethyl, aminomethyl, 2-hydroxyethyl, or3-hydroxypropyl and R^(f) is selected from hydroxy, fluoro, chloro,cyano. and methyl.
 44. The compound of any one of claims 1 to 41, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ isphenyl which is unsubstituted or substituted with R^(f) wherein R^(f) isfluoro, chloro, bromo, or methyl and wherein R^(f) is attached to carbonatoms on the phenyl ring that is ortho to the carbon atom of the phenylring attached to quinazolone nitrogen.
 45. The compound of any one ofclaims 1 to 41, or a pharmaceutically acceptable salt thereof whereinR^(t) is R⁷ wherein R⁷ is heteroaryl which is unsubstituted orsubstituted with R^(d), R^(e), and/or R^(f) where R^(d) and R^(e) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl, hydroxyalkyl,alkoxyalkyl, aminoalkyl, aminosulfonyl, alkylaminosulfonyl,dialkylaminosulfonyl, sulfonylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, heterocyclylcarbonyl, and ureido; and R^(f) isselected from alkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, andcyano,
 46. The compound of any one of claims 1 to 41, or apharmaceutically acceptable salt thereof wherein R¹ is R⁷ wherein R⁷ is5 or 6-membered heteroaryl ring such as pyrrolyl, pyrazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyridazinyl, or pyrazinyl, which isunsubstituted or substituted with R^(d) and/or R^(e) independentlyselected from methyl, ethyl, fluoro, chloro, bromo, methoxy, ethoxy,cyclopropyl, cyano, methylsulfonyl, methoxymethyl, aminomethyl,2-hydroxyethyl, or 3-hydroxypropyl and/or R^(f) selected from hydroxy,fluoro, chloro, cyano, and methyl.
 47. The compound of any one of claims1 to 41, or a pharmaceutically acceptable salt thereof wherein R¹pyridinyl which is unsubstituted or substituted with R^(f) wherein R^(f)is fluoro, chloro, bromo, or methyl and wherein R^(f) is attached tocarbon atoms on the pyridinyl ring that is ortho to the carbon atom ofthe pyridinyl ring attached to quinazolone nitrogen.
 48. The compound ofclaim 1 wherein the compound is selected from compounds 2-52, 54-83,85-97, 99-102, 104-106, 109, 112-129, 132-146, 148-151, 153-155, 157,159-165, 167-190, 192, 195-209, 211, 214, 216-228, 230-252, 255-287,289-304, 306-310, 312-339, 341-353, 355, 366-374, 376-387, 389-528,530-772 in Table 1 or a pharmaceutically acceptable salt thereof.
 49. Apharmaceutical composition comprising a compound of any one of claims 1to 48, or a pharmaceutically acceptable salt thereof at least onepharmaceutically acceptable excipient
 50. A method for treating adisease mediated by MAT2A in a patient comprising administering to thepatient a therapeutically effective amount of: (a) a compound of Formula(IIA″)

where: w is CR³ or N; x is CR⁴ or N; y is CR⁵ or N; and z is CR⁶ or N,wherein: R³ is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, alkylsulfonyl,halo, haloalkyl, haloalkoxy, cycloalkyl, cycloalkylalkyloxy, cyano,amino, alkylamino, dialkylamino, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, hydroxyalkyl, hydroxyalkoxy, hydroxyalkylamino,alkoxyalkyl, alkoxyalkoxy, alkoxyalkylamino, aminoalkyl, aminoalkoxy,aminoalkylamino, heteroaryl, heteroaryloxy, heteroaralkyloxy,heteroarylamino, heterocyclyl, heterocyclyloxy, heterocyclylamino,heterocyclylalkyloxy, heterocyclyloxyalkoxy, orheterocyclyloxyalkylamino, wherein heterocyclyl or heteroaryl, by itselfor as part of another group, is unsubstituted or substituted with R^(a),R^(b), and/or R^(c) independently selected from alkyl, cycloalkyl,haloalkyl, haloalkoxy, alkoxy, hydroxy, halo, cyano, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, or aminoalkyl; R⁵ is hydrogen, alkyl,alkenyl, alkynyl, alkoxy, alkylsulfonyl, halo, haloalkyl, haloalkoxy,cycloalkyl, cyano, amino, alkylamino, dialkylamino, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, hydroxyalkyl,hydroxyalkoxy, hydroxyalkylamino, alkoxyalkyl, alkoxyalkoxy,alkoxyalkylamino, aminoalkyl, aminoalkoxy, aminoalkylamino, heteroaryl,heteroaryloxy, heteroarylamino, heterocyclyl, heterocyclyloxy,heterocyclylamino, heterocyclyloxyalkoxy, or heterocyclyloxyalkylamino,wherein heterocyclyl or heteroaryl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(a), R^(b), and/or R^(c)independently selected from alkyl, cycloalkyl, haloalkyl, haloalkoxy,alkoxy, hydroxy, halo, cyano, hydroxyalkyl, alkoxyalkyl, or aminoalkyl;R⁴ and R⁶ are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy,alkylthio, alkylsulfonyl, halo, haloalkyl, haloalkoxy, cycloalkyl,cyano, amino, alkylamino, dialkylamino, aminocarbonyl,alkylaminocarbonyl, or dialkylaminocarbonyl; provided that: (i) no morethan two of w, x, y, and z can be N and (ii) at least one of R³, R⁴, R⁵,and R⁶ is other than hydrogen; R¹ is R⁷ wherein R⁷ is cycloalkyl,bridged cycloalkyl, fused cycloalkyl, spirocycloalkyl, aryl, heteroaryl,heterocyclyl, bridged heterocyclyl, fused heterocyclyl, orspiroheterocyclyl, wherein aryl, heteroaryl, or heterocyclyl isunsubstituted or substituted with R^(d), R^(e), and/or R^(f); R² isalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,aminocarbonylalkyl, aminosulfonylalkyl, —O—R⁸, —NR⁹R¹⁰, or —X^(b)—R¹¹wherein: R⁸ is alkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl,cycloalkyl, cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heterocyclyl, heterocyclylalkyl, heterocyclyloxyalkyl, fusedheterocyclyl, fused heterocyclylalkyl, bridged heterocyclyl, bridgedheterocyclylalkyl, spiroheterocyclyl, or spiroheterocyclylalkyl, whereinaryl, heteroaryl, or heterocyclyl, by itself or as part of anothergroup, is unsubstituted or substituted with R^(g), R^(h), and/or R^(i);R⁹ is hydrogen, alkyl, deuteroalkyl, or cycloalkyl; and R¹⁰ is hydrogen,alkyl, deuteroalkyl, haloalkyl, hydroxyalkyl, alkoxyalkyl,haloalkoxyalkyl, aminoalkyl, aminosulfonylalkyl, thioureidoalkyl,alkylsulfonyl, alkylsulfonylalkyl, cyanoalkyl, alkylcarbonyl,alkoxycarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl,aminocarbonylalkyl, cycloalkyl, cycloalkylalkyl, substituted cycloalkyl,substituted cycloalkylalkyl, cycloalkoxyalkyl, bridged cycloalkyl,bridged cycloalkylalkyl, fused cycloalkyl, spirocycloalkyl,spirocycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl,heteroarylcarbonyl, heterocyclyl, heterocyclylalkyl,heterocyclylcarbonyl, heterocyclyloxyalkyl, fused heterocyclyl, fusedheterocyclylalkyl, bridged heterocyclyl, bridged heterocyclylalkyl,spiroheterocyclyl, or spiroheterocyclylalkyl, wherein aryl, heteroaryl,or heterocyclyl, by itself or as part of another group, is unsubstitutedor substituted with R^(j), R^(k), and/or R^(l); X^(b) is a bond oralkylene; and R¹¹ is cycloalkyl, bridged cycloalkyl, fused cycloalkyl,spirocycloalkyl, heteroaryl, heterocyclyl, bridged heterocyclyl, fusedheterocyclyl, or spiroheterocyclyl, wherein heteroaryl or heterocyclylis unsubstituted or substituted with R^(m), R^(n), and/or R^(o); andR^(d), R^(e), R^(g), R^(h), R^(j), R^(k), R^(m), and R^(n) areindependently selected from alkyl, haloalkyl, haloalkoxy, alkoxy,hydroxy, alkylsulfonyl, halo, cyano, carboxy, alkoxycarbonyl,hydroxyalkyl, alkoxyalkyl, aminoalkyl, aminosulfonyl,alkylaminosulfonyl, dialkylaminosulfonyl, sulfonylamino, aminocarbonyl,alkylaminocarbonyl, dialkylaminocarbonyl, heterocyclylcarbonyl, andureido; and R^(f), R^(i), R^(l), and R^(o) are independently selectedfrom alkyl, cycloalkyl, haloalkyl, haloalkoxy, alkoxy, hydroxy, halo,amino, alkylamino, cycloalkylsulfonylamino, cyano, cyanoalkyl,alkoxycarbonylalkyl, carboxyalkyl, aminocarbonylalkyl, or —X^(c)—R¹²where X° is bond, alkylene, or heteroalkylene and R¹² is optionallysubstituted aryl, optionally substituted heteroaryl, and optionallysubstituted heterocyclyl; provided that when R¹ is heterocyclyl then Ris not hydroxy; or (b) a compound of any one of claims 2 to 47; apharmaceutically acceptable salt thereof.
 51. The method of claim 50,wherein the disease is cancer.
 52. A method of treating a MTAP nullcancer in a patient comprising administering to the patient atherapeutically effective amount of a compound of Formula (IA′) asdefined in claim 49 or a compound of any one of claims 2 to 48; apharmaceutically acceptable salt thereof optionally in a pharmaceuticalcomposition.
 53. A method for treating a cancer in a patient, whereinthe cancer is characterized by a reduction or absence of MTAP geneexpression, the absence of the MTAP gene, or reduced function of MTAPprotein, comprising administering to the subject a therapeuticallyeffective amount of of a compound of a compound of Formula (IA′) asdefined in claim 49 or a compound of any one of claims 2 to 48; apharmaceutically acceptable salt thereof optionally in a pharmaceuticalcomposition.
 54. The method of any one of claims 51 to 53 wherein thecancer is leukemia, glioma, melanoma, pancreatic, non-small cell lungcancer, bladder cancer, astrocytoma, osteosarcoma, head and neck cancer,myxoid chondrosarcoma, ovarian cancer, endometrial cancer, breastcancer, soft tissue sarcoma, non-Hodgkin lymphoma or mesothelioma.